47 results on '"Smith, Jeremy C."'
Search Results
2. Low frequency enzyme dynamics as a function of temperature and hydration: A neutron scattering study
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Kurkal, V., Daniel, R.M., Finney, John L., Tehei, M., Dunn, R.V., and Smith, Jeremy C.
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- 2005
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3. Convergence properties of X-ray scattering calculated from protein crystal molecular dynamics simulations
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Meinhold, Lars, Lammers, Sven, Becker, Torsten, and Smith, Jeremy C
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- 2004
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4. Use of computer simulation in the interpretation of elastic neutron scattering in complex molecular systems: a small protein in various environments
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Hayward, Jennifer A., Daniel, Roy M., Finney, John L., and Smith, Jeremy C.
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- 2003
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5. Protein hydration water: Structure and thermodynamics
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Smith, Jeremy C., Merzel, Franci, Verma, Chandra S., and Fischer, Stefan
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- 2002
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6. The importance of the membrane interface as the reference state for membrane protein stability.
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Ulmschneider, Jakob P., Smith, Jeremy C., White, Stephen H., and Ulmschneider, Martin B.
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MEMBRANE proteins , *MOLECULAR dynamics , *POLYPEPTIDES , *AMINO acids , *CYCLOHEXANE - Abstract
Abstract The insertion of nascent polypeptide chains into lipid bilayer membranes and the stability of membrane proteins crucially depend on the equilibrium partitioning of polypeptides. For this, the transfer of full sequences of amino-acid residues into the bilayer, rather than individual amino acids, must be understood. Earlier studies have revealed that the most likely reference state for partitioning very hydrophobic sequences is the membrane interface. We have used μs-scale simulations to calculate the interface-to-transmembrane partitioning free energies ΔG S→TM for two hydrophobic carrier sequences in order to estimate the insertion free energy for all 20 amino acid residues when bonded to the center of a partitioning hydrophobic peptide. Our results show that prior single-residue scales likely overestimate the partitioning free energies of polypeptides. The correlation of ΔG S→TM with experimental full-peptide translocon insertion data is high, suggesting an important role for the membrane interface in translocon-based insertion. The choice of carrier sequence greatly modulates the contribution of each single-residue mutation to the overall partitioning free energy. Our results demonstrate the importance of quantifying the observed full-peptide partitioning equilibrium, which is between membrane interface and transmembrane inserted, rather than combining individual water-to-membrane amino acid transfer free energies. Graphical abstract Unlabelled Image Highlights • The insertion of polypeptide chains into lipid bilayer membranes depends on the interface-to-transmembrane free energies for full peptides • Long-scale fully atomistic simulations now allow direct computation of fullpeptide insertion free energies • Correlation with full-peptide translocon insertion data suggests an important role for the membrane interface in translocon-based insertion. • The relevant reference state for membrane insertion is the surface state, rather than a water soluble state [ABSTRACT FROM AUTHOR]
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- 2018
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7. Role of magnesium ions in DNA recognition by the EcoRV restriction endonuclease
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Zahran, Mai, Berezniak, Tomasz, Imhof, Petra, and Smith, Jeremy C.
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- 2011
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8. Lateral organization, bilayer asymmetry, and inter-leaflet coupling of biological membranes.
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Nickels, Jonathan D., Smith, Jeremy C., and Cheng, Xiaolin
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BIOLOGICAL membranes , *BILAYER lipid membranes , *SYMMETRY (Biology) , *CELL membranes , *CELLULAR signal transduction - Abstract
Understanding of cell membrane organization has evolved significantly from the classic fluid mosaic model. It is now recognized that biological membranes are highly organized structures, with differences in lipid compositions between inner and outer leaflets and in lateral structures within the bilayer plane, known as lipid rafts. These organizing principles are important for protein localization and function as well as cellular signaling. However, the mechanisms and biophysical basis of lipid raft formation, structure, dynamics and function are not clearly understood. One key question, which we focus on in this review, is how lateral organization and leaflet compositional asymmetry are coupled. Detailed information elucidating this question has been sparse because of the small size and transient nature of rafts and the experimental challenges in constructing asymmetric bilayers. Resolving this mystery will require advances in both experimentation and modeling. We discuss here the preparation of model systems along with experimental and computational approaches that have been applied in efforts to address this key question in membrane biology. We seek to place recent and future advances in experimental and computational techniques in context, providing insight into in-plane and transverse organization of biological membranes. [ABSTRACT FROM AUTHOR]
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- 2015
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9. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
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Abraham, Mark James, Murtola, Teemu, Schulz, Roland, Páll, Szilárd, Smith, Jeremy C., Hess, Berk, and Lindahl, Erik
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- 2015
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10. Tri-peptide reference structures for the calculation of relative solvent accessible surface area in protein amino acid residues.
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Topham, Christopher M. and Smith, Jeremy C.
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PROTEIN structure , *AMINO acid residues , *SOLVENTS , *SUBSTITUENTS (Chemistry) , *COMPARATIVE studies , *QUANTUM chemistry , *PEPTIDE analysis - Abstract
Relative amino acid residue solvent accessibility values allow the quantitative comparison of atomic solvent-accessible surface areas in different residue types and physical environments in proteins and in protein structural alignments. Geometry-optimised tri-peptide structures in extended solvent-exposed reference conformations have been obtained for 43 amino acid residue types at a high level of quantum chemical theory. Significant increases in side-chain solvent accessibility, offset by reductions in main-chain atom solvent exposure, were observed for standard residue types in partially geometry-optimised structures when compared to non-minimised models built from identical sets of proper dihedral angles abstracted from the literature. Optimisation of proper dihedral angles led most notably to marked increases of up to 54% in proline main-chain atom solvent accessibility compared to literature values. Similar effects were observed for fully-optimised tri-peptides in implicit solvent. The relief of internal strain energy was associated with systematic variation in N, C α and C β atom solvent accessibility across all standard residue types. The results underline the importance of optimisation of ‘hard’ degrees of freedom (bond lengths and valence bond angles) and improper dihedral angle values from force field or other context-independent reference values, and impact on the use of standardised fixed internal co-ordinate geometry in sampling approaches to the determination of absolute values of protein amino acid residue solvent accessibility. Quantum chemical methods provide a useful and accurate alternative to molecular mechanics methods to perform energy minimisation of peptides containing non-standard (chemically modified) amino acid residues frequently present in experimental protein structure data sets, for which force field parameters may not be available. Reference tri-peptide atomic co-ordinate sets including hydrogen atoms are made freely available. [ABSTRACT FROM AUTHOR]
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- 2015
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11. Structural asymmetry in FGF23 signaling.
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Liu, Shih-Hsien, Xiao, Zhousheng, Smith, Jeremy C., and Quarles, L. Darryl
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FIBROBLAST growth factor receptors , *FIBROBLAST growth factors , *DRUG design - Abstract
Chen et al. have derived cryogenic electron microscopy (cryo-EM) structures of signaling complexes of the endocrine hormone fibroblast growth factor 23 (FGF23) with fibroblast growth factor receptor (FGFR), α-Klotho, and heparin sulfate. These structures are asymmetric, leading to questions concerning in vivo function, and will facilitate structure-based drug design to modulate FGF23 signaling. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Eppur Si Muove! The 2013 Nobel Prize in Chemistry.
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Smith, Jeremy?C. and Roux, Benoît
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NOBEL Prizes , *COMPUTATIONAL chemistry , *CHEMICAL structure - Abstract
The 2013 Nobel Prize in Chemistry has been awarded to Martin Karplus, Michael Levitt, and Arieh Warshel for their work on developing computational methods to study complex chemical systems. Their work has led to mechanistic critical insights into chemical systems both large and small and has enabled progress in a number of different fields, including structural biology. [ABSTRACT FROM AUTHOR]
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- 2013
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13. Kinetics of breaking a salt-bridge critical in protein unfolding
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Gruia, Andreea D., Fischer, Stefan, and Smith, Jeremy C.
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- 2004
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14. Partitioning of amino-acid analogues in a five-slab membrane model
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Sengupta, Durba, Smith, Jeremy C., and Ullmann, G. Matthias
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SOLUTION (Chemistry) , *AMINO acids , *AMINO compounds , *ORGANIC acids - Abstract
Abstract: The positional preferences of the twenty amino-acid residues in a phospholipid bilayer are investigated by calculating the solvation free energy of the corresponding side chain analogues using a five-slab continuum electrostatic model. The side-chain analogues of the aromatic residues tryptophan and tyrosine are found to partition in the head-group region, due to compensation between the increase of the non-polar component of the solvation free energy at the boundary with the aqueous region and the decrease in the electrostatic component. The side chain analogue of phenylalanine differs from the other aromatic molecules by being able to partition in both the head-group region and the membrane core. This finding is consistent with experimental findings of the position of phenylalanine in membrane helices. Interestingly, the charged side-chain analogues of arginine and lysine are shown to prefer the head-group region in an orientation that allows the charged moiety to interact with the aqueous layer. The orientation adopted is similar to the “snorkelling” effect seen in lysine and arginine residues in membrane helices. In contrast, the preference of the charged side-chain analogues of histidine (protonated) and aspartate (deprotonated) for the aqueous layer is shown to be due to a steep decrease in the electrostatic component of the solvation free energy at the boundary to the aqueous region. The calculations allow an understanding of the origins of side chain positioning in membranes and are thus useful in understanding membrane–protein:lipid thermodynamics. [Copyright &y& Elsevier]
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- 2008
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15. The Structural Coupling between ATPase Activation and Recovery Stroke in the Myosin II Motor
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Koppole, Sampath, Smith, Jeremy C., and Fischer, Stefan
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ADENOSINE triphosphatase , *MYOSIN , *MUSCLE proteins , *PHOSPHATASES - Abstract
Summary: Before the myosin motor head can perform the next power stroke, it undergoes a large conformational transition in which the converter domain, bearing the lever arm, rotates ∼65°. Simultaneous with this “recovery stroke,” myosin activates its ATPase function by closing the Switch-2 loop over the bound ATP. This coupling between the motions of the converter domain and of the 40 Å-distant Switch-2 loop is essential to avoid unproductive ATP hydrolysis. The coupling mechanism is determined here by finding a series of optimized intermediates between crystallographic end structures of the recovery stroke (Dictyostelium discoideum), yielding movies of the transition at atomic detail. The successive formation of two hydrogen bonds by the Switch-2 loop is correlated with the successive see-saw motions of the relay and SH1 helices that hold the converter domain. SH1 helix and Switch-2 loop communicate via a highly conserved loop that wedges against the SH1-helix upon Switch-2 closing. [Copyright &y& Elsevier]
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- 2007
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16. A MOSFET power supply clamp with feedback enhanced triggering for ESD protection in advanced CMOS technologies
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Smith, Jeremy C. and Boselli, Gianluca
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POWER resources , *ELECTRONICS , *BEHAVIOR - Abstract
A novel power supply protection clamp is presented which incorporates feedback techniques to improve ESD and normal operational mode behavior. The design uses a short duration RC trigger, which enables the clamp to tolerate very fast power supply ramp rates and exhibit reduced area and leakage. The design is built in a 90 nm CMOS technology with fully salicided source/drain regions. [Copyright &y& Elsevier]
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- 2005
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17. Sassena — X-ray and neutron scattering calculated from molecular dynamics trajectories using massively parallel computers
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Lindner, Benjamin and Smith, Jeremy C.
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MOLECULAR dynamics , *X-rays , *NEUTRON scattering , *TRAJECTORIES (Mechanics) , *DATA analysis , *PROBLEM solving , *PARALLEL computers - Abstract
Abstract: Massively parallel computers now permit the molecular dynamics (MD) simulation of multi-million atom systems on time scales up to the microsecond. However, the subsequent analysis of the resulting simulation trajectories has now become a high performance computing problem in itself. Here, we present software for calculating X-ray and neutron scattering intensities from MD simulation data that scales well on massively parallel supercomputers. The calculation and data staging schemes used maximize the degree of parallelism and minimize the IO bandwidth requirements. The strong scaling tested on the Jaguar Petaflop Cray XT5 at Oak Ridge National Laboratory exhibits virtually linear scaling up to 7000 cores for most benchmark systems. Since both MPI and thread parallelism is supported, the software is flexible enough to cover scaling demands for different types of scattering calculations. The result is a high performance tool capable of unifying large-scale supercomputing and a wide variety of neutron/synchrotron technology. Program summary: Program title: Sassena Catalogue identifier: AELW_v1_0 Program summary URL: http://cpc.cs.qub.ac.uk/summaries/AELW_v1_0.html Program obtainable from: CPC Program Library, Queenʼs University, Belfast, N. Ireland Licensing provisions: GNU General Public License, version 3 No. of lines in distributed program, including test data, etc.: 1 003 742 No. of bytes in distributed program, including test data, etc.: 798 Distribution format: tar.gz Programming language: C++, OpenMPI Computer: Distributed Memory, Cluster of Computers with high performance network, Supercomputer Operating system: UNIX, LINUX, OSX Has the code been vectorized or parallelized?: Yes, the code has been parallelized using MPI directives. Tested with up to 7000 processors RAM: Up to 1 Gbytes/core Classification: 6.5, 8 External routines: Boost Library, FFTW3, CMAKE, GNU C++ Compiler, OpenMPI, LibXML, LAPACK Nature of problem: Recent developments in supercomputing allow molecular dynamics simulations to generate large trajectories spanning millions of frames and thousands of atoms. The structural and dynamical analysis of these trajectories requires analysis algorithms which use parallel computation and IO schemes to solve the computational task in a practical amount of time. The particular computational and IO requirements very much depend on the particular analysis algorithm. In scattering calculations a very frequent pattern is that the trajectory data is used multiple times to compute different projections and aggregates this into a single scattering function. Thus, for good performance the trajectory data has to be kept in memory and the parallel computer has to have enough RAM to store a volatile version of the whole trajectory. In order to achieve high performance and good scalability the mapping of the physical equations to a parallel computer needs to consider data locality and reduce the amount of the inter-node communication. Solution method: The physical equations for scattering calculations were analyzed and two major calculation schemes were developed to support any type of scattering calculation (all/self). Certain hardware aspects were taken into account, e.g. high performance computing clusters and supercomputers usually feature a 2 tier network system, with Ethernet providing the file storage and infiniband the inter-node communication via MPI calls. The time spent loading the trajectory data into memory is minimized by letting each core only read the trajectory data it requires. The performance of inter-node communication is maximized by exclusively utilizing the appropriate MPI calls to exchange the necessary data, resulting in an excellent scalability. The partitioning scheme developed to map the calculation onto a parallel computer covers a wide variety of use cases without negatively effecting the achieved performance. This is done through a 2D partitioning scheme where independent scattering vectors are assigned to independent parallel partitions and all communication is local to the partition. Additional comments: !!!!! The distribution file for this program is approximately 36 Mbytes and therefore is not delivered directly when download or E-mail is requested. Instead an html file giving details of how the program can be obtained is sent. !!!!! Running time: Usual runtime spans from 1 min on 20 nodes to 2 h on 2000 nodes. That is 0.5–4000 CPU hours per execution. [Copyright &y& Elsevier]
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- 2012
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18. REACH: A program for coarse-grained biomolecular simulation
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Moritsugu, Kei and Smith, Jeremy C.
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MOLECULAR dynamics , *COMPUTER software , *COMPUTER simulation , *PROTEIN analysis , *BIOMOLECULES , *MATRICES (Mathematics) - Abstract
Abstract: REACH (Realistic Extension Algorithm via Covariance Hessian) is a program package for residue-scale coarse-grained biomolecular simulation. The program calculates the force constants of a residue-scale elastic network model in single-domain proteins using the variance–covariance matrix obtained from atomistic molecular dynamics simulation. Secondary-structure dependence of the force constants is integrated. The method involves self-consistent, direct mapping of atomistic simulation results onto a coarse-grained force field in an efficient automated procedure without requiring iterative fits and avoiding system dependence. Program summary: Program title: REACH Catalogue identifier: AEDA_v1_0 Program summary URL: http://cpc.cs.qub.ac.uk/summaries/AEDA_v1_0.html Program obtainable from: CPC Program Library, Queen''s University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 42 244 No. of bytes in distributed program, including test data, etc.: 3 682 118 Distribution format: tar.gz Programming language: FORTRAN 77 Computer: x86 PC Operating system: GNU/Linux, SUSE and Red Hat RAM: Depends on the system size to be calculated Word size: 32 or 64 bits Classification: 3 External routines: LAPACK, BLAS Nature of problem: A direct calculation of force field for residue-scale coarse-grained biomolecular simulation derived from atomistic molecular dynamics trajectory. Solution method: A variance–covariance matrix and the associated Hessian (second-derivative) matrix are calculated from an atomistic molecular dynamics trajectory of single-domain protein internal motion and the off-diagonal Hessian matrix is fitted to that of a residue-scale elastic network model. The resulting force constants for the residue pair interactions are expressed as model functions as a function of pairwise distance. Running time: Depends on the system size and the number of MD trajectory frames used. The test run provided with the distribution takes only a few seconds to execute. [Copyright &y& Elsevier]
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- 2009
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19. Effects of sodium and calcium chloride ionic stresses on model yeast membranes revealed by molecular dynamics simulation.
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Smith, Micholas Dean and Smith, Jeremy C.
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CALCIUM chloride , *MOLECULAR dynamics , *YEAST , *WASTE products , *CELL membranes - Abstract
• NaCl and CaCl 2 stresses weakly modulate yeast plasma membrane morphology. • Both salts impact membrane dynamics. • CaCl 2 is found to have a more substantial impact than NaCl. As efforts to move a renewable economy grow, it will be necessary to make use of microbial conversion strategies for the production of novel materials or the upgrading of waste to high-value products. One critical technical challenge currently limiting waste upgrading remains the difficulty in obtaining single-pot conversion techniques where physical, chemical, and biological conversion are performed in a single step. To overcome this challenge, a detailed understanding of how different stresses impact microbial membrane stability will be necessary. Using all-atom molecular dynamics simulations, we examine the impacts of moderate concentrations of NaCl and CaCl 2 on a model yeast plasma membrane. Weak, though statistically significant, changes in membrane morphology and dynamics functions are observed that are consistent with swelling and stiffening. Additionally, an examination of the ion-lipid contacts and the behavior of water at the water-membrane interface suggests that the impacts of these common salts may, in part, be mediated through changes to water-membrane hydrogen-bonding and hydration water dynamics. [ABSTRACT FROM AUTHOR]
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- 2020
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20. Four countries for science.
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Smith, Jeremy C.
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COUNTRIES , *SCIENCE - Abstract
A personal retrospect is given on four decades in science in four countries - the UK, France, Germany and the USA. Some historical observations are made together with a time transect through scientific systems and institutions in the four countries. [ABSTRACT FROM AUTHOR]
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- 2020
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21. Tight in Titin
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Smith, Jeremy C.
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PROTEINS , *STRIATED muscle , *ELASTIC tissue , *COMPUTER simulation - Abstract
The mechanics of a protein joint, gluing two elastic titin molecules together in muscle, are explored using computer simulation in this issue of Structure by . Maybe the glue itself also has another, more subtle, sensory role? [Copyright &y& Elsevier]
- Published
- 2006
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22. Structure-guided design of a broadly cross-reactive multivalent group a streptococcal vaccine.
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Dale, James B., Aranha, Michelle P., Penfound, Thomas A., Salehi, Sanaz, and Smith, Jeremy C.
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STREPTOCOCCAL diseases , *PEPTIDES , *VACCINATION coverage , *EPITOPES , *VACCINES , *IMMUNOGLOBULINS - Abstract
• There is a global need for broadly protective group A streptococcal vaccines. • M protein-based subunit vaccines elicit M-type cross-reactive antibodies. • Structure-based design of multivalent vaccines improves potential coverage. • A 32-valent vaccine could prevent the majority of group A streptococcal infections. The M protein of group A streptococci (Strep A) is a major virulence determinant and protective antigen. The N-terminal region of the M protein is variable in sequence, defines the M/emm type, and contains epitopes that elicit opsonic antibodies that protect animals from challenge infections. Although there are >200 M types of Strep A, there is now evidence that structurally related M proteins can be grouped into clusters and that immunity may be cluster-specific in addition to M type-specific. This observation has led to recent studies of structure-based design of multivalent M peptide vaccines to select peptides predicted to cross-react with heterologous M types to improve vaccine coverage. In the current study, we have applied a refined series of peptide structural algorithms to predict immunological cross-reactivity among 117 N-terminal M peptides representing the most prevalent M types of Strep A. Based on the results of the structural analyses, in combination with global M type prevalence data, we constructed a 32-valent vaccine containing 19 cross-reactive vaccine candidates predicted to cross-react with 37 heterologous M peptides to which were added 13 type-specific M peptides. The 4-protein recombinant vaccine was immunogenic in rabbits and elicited significant levels of antibodies against 31/32 (97%) vaccine peptides and 28/37 (76%) peptides predicted to cross-react. The vaccine antisera also promoted opsonophagocytic killing of vaccine and cross-reactive M types of Strep A. Based on a recent analysis of M type prevalence of Strep A, the potential global coverage of the 32-valent vaccine is ∼90%, ranging from 68% in Africa to 95% in North America. Our results indicate the utility of structure-based design that may be applied to future studies of broadly protective M peptide vaccines. [ABSTRACT FROM AUTHOR]
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- 2023
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23. Dynamics of proteins: Correlation and diffusion
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Héry, Stéphanie, Genest, Daniel, and Smith, Jeremy C.
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- 1997
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24. Molecular mechanics analysis of peptide group hydrogen bonding cooperativity and influence on Φand Ψ rotational barriers
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Baudry, Jérôme and Smith, Jeremy C.
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- 1994
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25. SERENA: a program for calculating X-ray diffuse scattering intensities from molecular dynamics trajectories
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Micu, Alexandru M. and Smith, Jeremy C.
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- 1995
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26. Conformational energetics of a partially symmetrized photosynthetic reaction centre
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Foloppe, Nicolas, Breton, Jacques, and Smith, Jeremy C.
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- 1995
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27. The α Helix Dipole: Screened Out?
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Sengupta, Durba, Behera, Raghu Nath, Smith, Jeremy C., and Ullmann, G. Matthias
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PROTEIN folding , *PEPTIDE synthesis , *DIPOLE moments , *PROTEINS , *ELECTROSTATICS - Abstract
Summary: Aligned α helix peptide dipoles sum to a “macroscopic” dipole parallel to the helix axis that has been implicated in protein folding and function. However, in aqueous solution the dipole is counteracted by an electrostatic reaction field generated by the solvent, and the strength of the helix dipole may reduce drastically from its value in vacuum. Here, using atomic-detail helix models and Poisson-Boltzmann continuum electrostatics calculations, the net effective dipole moment, μeff, is calculated. Some initially surprising results are found. Whereas in vacuum μeff increases with helix length, the opposite is found to be the case for transmembrane helices. In soluble proteins, μeff is found to vary strongly with the orientation and position of the helix relative to the aqueous medium. A set of rules is established to estimate of the strength of μeff from graphical inspection of protein structures. [Copyright &y& Elsevier]
- Published
- 2005
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28. Mechanism of a Molecular Valve in the Halorhodopsin Chloride Pump
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Gruia, Andreea D., Bondar, Ana-Nicoleta, Smith, Jeremy C., and Fischer, Stefan
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CELL membranes , *BIOLOGICAL membranes , *CHLORIDES , *CHROMOSOMAL translocation , *CHROMOSOMES - Abstract
Summary: Halorhodopsin is a light-driven chloride anion pump in which the trans→cis photoisomerization of a retinal chromophore triggers a photocyle resulting in the translocation of chloride across the plasma membrane. The mechanism of chloride transfer past the cis retinal is determined here by computing multiple pathways for this process. The calculations reveal two conditions of the valve mechanism. First, a lumen absent in the ground state structure is transiently opened by chloride passage. Second, this activated opening, which is achieved by flexible deformation of the surrounding protein, is shown to significantly raise the chloride translocation barrier between photocycles, thus preventing chloride backflow. Unlike macroscopic valve designs, the protein allows differential ion flows in the pumping and resting states that are tuned to match the physiological timescales of the cell, thus creating a “kinetic” valve. [Copyright &y& Elsevier]
- Published
- 2005
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29. Drugging the entire human proteome: Are we there yet?
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Smith, Micholas Dean, Darryl Quarles, L., Demerdash, Omar, and Smith, Jeremy C.
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PROTEIN structure , *HUMAN beings - Abstract
• On the feasibility of human-proteome VHTS. • Highlights of pitfalls and outlook. Each of the ∼20,000 proteins in the human proteome is a potential target for compounds that bind to it and modify its function. The 3D structures of most of these proteins are now available. Here, we discuss the prospects for using these structures to perform proteome-wide virtual HTS (VHTS). We compare physics-based (docking) and AI VHTS approaches, some of which are now being applied with large databases of compounds to thousands of targets. Although preliminary proteome-wide screens are now within our grasp, further methodological developments are expected to improve the accuracy of the results. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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30. Cross-reactive immunogenicity of group A streptococcal vaccines designed using a recurrent neural network to identify conserved M protein linear epitopes.
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Spencer, Jay A., Penfound, Tom, Salehi, Sanaz, Aranha, Michelle P., Wade, Lauren E., Agarwal, Rupesh, Smith, Jeremy C., Dale, James B., and Baudry, Jerome
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RECURRENT neural networks , *EPITOPES , *STREPTOCOCCAL diseases , *RECOMBINANT proteins , *PEPTIDOMIMETICS - Abstract
The M protein of group A streptococci (Strep A) is a major virulence determinant and protective antigen. The N-terminal sequence of the protein defines the more than 200 M types of Strep A and also contains epitopes that elicit opsonic antibodies, some of which cross-react with heterologous M types. Current efforts to develop broadly protective M protein-based vaccines are directed at identifying potential cross-protective epitopes located in the N-terminal regions of cluster-related M proteins for use as vaccine antigens. In this study, we have used a comprehensive approach using the recurrent neural network ABCpred and IEDB epitope conservancy analysis tools to predict 16 residue linear B-cell epitopes from 117 clinically relevant M types of Strep A (~88% of global Strep A infections). To examine the immunogenicity of these epitope-based vaccines, nine peptides that together shared ≥60% sequence identity with 37 heterologous M proteins were incorporated into two recombinant hybrid protein vaccines, in which the epitopes were repeated 2 or 3 times, respectively. The combined immune responses of immunized rabbits showed that the vaccines elicited significant levels of antibodies against all nine vaccine epitopes present in homologous N-terminal 1–50 amino acid synthetic M peptides, as well as cross-reactive antibodies against 16 of 37 heterologous M peptides predicted to contain similar epitopes. The epitope-specificity of the cross-reactive antibodies was confirmed by ELISA inhibition assays and functional opsonic activity was assayed in HL-60-based bactericidal assays. The results provide important information for the future design of broadly protective M protein-based Strep A vaccines. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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31. Structure-based group A streptococcal vaccine design: Helical wheel homology predicts antibody cross-reactivity among streptococcal M protein-derived peptides.
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Aranha, Michelle P., Penfound, Thomas A., Spencer, Jay A., Agarwal, Rupesh, Baudry, Jerome, Dale, James B., and Smith, Jeremy C.
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PEPTIDES , *VACCINES , *HOMOLOGY (Biology) , *IMMUNE serums , *IMMUNOGLOBULINS - Abstract
Group A streptococcus (Strep A) surface M protein, an α-helical coiled-coil dimer, is a vaccine target and a major determinant of streptococcal virulence. The sequence-variable N-terminal region of the M protein defines the M type and also contains epitopes that promote opsonophagocytic killing of streptococci. Recent reports have reported considerable cross-reactivity among different M types, suggesting the prospect of identifying cross-protective epitopes that would constitute a broadly protective multivalent vaccine against Strep A isolates. Here, we have used a combination of immunological assays, structural biology, and cheminformatics to construct a recombinant M protein-based vaccine that included six Strep A M peptides that were predicted to elicit antisera that would cross-react with an additional 15 nonvaccine M types of Strep A. Rabbit antisera against this recombinant vaccine cross-reacted with 10 of the 15 nonvaccine M peptides. Two of the five nonvaccine M peptides that did not cross-react shared high sequence identity (≥50%) with the vaccine peptides, implying that high sequence identity alone was insufficient for cross-reactivity among the M peptides. Additional structural analyses revealed that the sequence identity at corresponding polar helical-wheel heptad sites between vaccine and nonvaccine peptides accurately distinguishes cross-reactive from non-cross-reactive peptides. On the basis of these observations, we developed a scoring algorithm based on the sequence identity at polar heptad sites. When applied to all epidemiologically important M types, this algorithm should enable the selection of a minimal number of M peptide-based vaccine candidates that elicit broadly protective immunity against Strep A. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
32. A probabilistic perspective on thermodynamic parameter uncertainties: Understanding aqueous speciation of mercury.
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Guo, Luanjing, Painter, Scott L., Brooks, Scott C., Parks, Jerry M., and Smith, Jeremy C.
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MONTE Carlo method , *MERCURY , *LOGNORMAL distribution , *LATIN hypercube sampling , *PROBABILITY density function , *CHEMICAL speciation , *METALLIC surfaces - Abstract
Speciation plays an important role in determining the fate and transport of metals in terrestrial surface and subsurface systems. Equilibrium speciation modeling in aqueous systems relies on thermodynamic constants (log K values) of complexes, which are subject to uncertainties. Here, using Monte Carlo (MC) simulations with Latin hypercube sampling (LHS) we systematically analyze the propagation of thermodynamic constant uncertainty through speciation modeling of an inorganic mercury-sulfide-chloride-water system. We find that seemingly small variances of the input log K normal distributions can lead to output species concentrations spanning multiple orders of magnitude, with highly skewed probability distributions. When equilibrium with mineral metacinnabar (β-HgS(s)) is neglected, the relative uncertainty of each output species is strongly positively correlated with the skewness of its concentration probability distribution, i.e., the lowest uncertainty occurs when the species concentration probability distribution is the most negatively skewed as its concentration approaches the total element concentration limit. The highest uncertainty in the identity of dominant species is located around species equivalence points. For cases where the mineral equilibrium is included, we derive analytical probability density functions for the log concentrations of all major species in the system. The mineral log K uncertainty is found to be an important contributor to all output concentration uncertainties. The analysis of combined effects of both pH and total sulfide concentration on output concentration uncertainties shows that high concentration uncertainties occur under highly sulfidic alkaline conditions and low uncertainties at low pH and sulfide concentrations. An analysis as presented here can distinguish between conditions that require a full uncertainty analysis and those for which the classical deterministic speciation modeling suffices. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
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33. Targeted inhibition of MASTL kinase activity induces apoptosis in breast cancer.
- Author
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Misra, Gauri, Rajawat, Jyotika, Pal, Rajesh, Smith, Jeremy C., and Kumar, Amit
- Subjects
- *
BREAST cancer , *APOPTOSIS , *CANCER cells , *MOLECULAR dynamics , *CELL cycle , *LEAD compounds , *RNA sequencing - Abstract
Microtubule-associated serine/threonine kinase-like (MASTL) (or Greatwall kinase (GWL)) is an important cell cycle regulating kinase that regulates the G2-M transition. Uncontrolled MASTL activity is implicated in breast cancer progression. To date, very few inhibitors have been reported against this protein. Here, structure-based computational modeling indicates that the natural product flavopiridol (FLV) binds strongly to MASTL and these results are validated using molecular dynamics simulation studies. An in vitro kinase assay reveals an EC 50 (effective concentration) value of FLV to be 82.1 nM and a better IC 50 compared to the positive reference compound, staurosporine. FLV is found to inhibit MASTL kinase activity, arresting the cell growth in the G1 phase and inducing apoptosis in breast cancer cells. Consistent with these results differential gene expression obtained using RNA sequencing studies, and validated by RT PCR and immunoblot analysis, indicate that MASTL inhibition induces cell cycle arrest and apoptotic-related genes. Furthermore, metastasis- and inflammation-related genes are downregulated. Thus, the deregulation of MASTL signaling pathways on targeted inhibition of its kinase activity is revealed. This study lays a strong foundation for investigating FLV as a lead compound in breast cancer therapeutics. • Microtubule-associated serine/threonine kinase-like (MASTL) is an important drug target in breast cancer that regulates G2-M transition. • Flavopiridol-mediated inhibition of MASTL kinase activity causes G1 arrest resulting in apoptosis. • Various metastasis and inflammation-related genes are differentially regulated on MASTL inhibition. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
34. Structure-based design of broadly protective group a streptococcal M protein-based vaccines.
- Author
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Dale, James B., Smeesters, Pierre R., Courtney, Harry S., Penfound, Thomas A., Hohn, Claudia M., Smith, Jeremy C., and Baudry, Jerome Y.
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VIRAL proteins , *VIRAL vaccines , *EPITOPES , *BACTERICIDES , *IMMUNE response - Abstract
Background A major obstacle to the development of broadly protective M protein-based group A streptococcal (GAS) vaccines is the variability within the N-terminal epitopes that evoke potent bactericidal antibodies. The concept of M type-specific protective immune responses has recently been challenged based on the observation that multivalent M protein vaccines elicited cross-reactive bactericidal antibodies against a number of non-vaccine M types of GAS. Additionally, a new “cluster-based” typing system of 175 M proteins identified a limited number of clusters containing closely related M proteins. In the current study, we used the emm cluster typing system, in combination with computational structure-based peptide modeling, as a novel approach to the design of potentially broadly protective M protein-based vaccines. Methods M protein sequences (AA 16–50) from the E4 cluster containing 17 emm types of GAS were analyzed using de novo 3-D structure prediction tools and the resulting structures subjected to chemical diversity analysis to identify sequences that were the most representative of the 3-D physicochemical properties of the M peptides in the cluster. Five peptides that spanned the range of physicochemical attributes of all 17 peptides were used to formulate synthetic and recombinant vaccines. Rabbit antisera were assayed for antibodies that cross-reacted with E4 peptides and whole bacteria by ELISA and for bactericidal activity against all E4G AS. Results The synthetic vaccine rabbit antisera reacted with all 17 E4 M peptides and demonstrated bactericidal activity against 15/17 E4G AS. A recombinant hybrid vaccine containing the same E4 peptides also elicited antibodies that cross-reacted with all E4 M peptides. Conclusions Comprehensive studies using structure-based design may result in a broadly protective M peptide vaccine that will elicit cluster-specific and emm type-specific antibody responses against the majority of clinically relevant emm types of GAS. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
35. Quasielastic neutron scattering in biology: Theory and applications.
- Author
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Vural, Derya, Hu, Xiaohu, Lindner, Benjamin, Jain, Nitin, Miao, Yinglong, Cheng, Xiaolin, Liu, Zhuo, Hong, Liang, and Smith, Jeremy C.
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QUASIELASTIC neutron scattering , *MOLECULAR dynamics , *LIPIDS , *PROTEINS , *BIOLOGICAL systems - Abstract
Neutrons scatter quasielastically from stochastic, diffusive processes, such as overdamped vibrations, localized diffusion and transitions between energy minima. In biological systems, such as proteins and membranes, these relaxation processes are of considerable physical interest. We review here recent methodological advances and applications of quasielastic neutron scattering (QENS) in biology, concentrating on the role of molecular dynamics simulation in generating data with which neutron profiles can be unambiguously interpreted. We examine the use of massively-parallel computers in calculating scattering functions, and the application of Markov state modeling. The decomposition of MD-derived neutron dynamic susceptibilities is described, and the use of this in combination with NMR spectroscopy. We discuss dynamics at very long times, including approximations to the infinite time mean-square displacement and nonequilibrium aspects of single-protein dynamics. Finally, we examine how neutron scattering and MD can be combined to provide information on lipid nanodomains. This article is part of a Special Issue entitled “Science for Life” Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
36. Ensemble-based docking: From hit discovery to metabolism and toxicity predictions.
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Evangelista, Wilfredo, Weir, Rebecca L., Ellingson, Sally R., Harris, Jason B., Kapoor, Karan, Smith, Jeremy C., and Baudry, Jerome
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MOLECULAR docking , *METABOLISM , *TOXICITY testing , *SUPERCOMPUTERS , *CLINICAL trials - Abstract
This paper describes and illustrates the use of ensemble-based docking, i.e., using a collection of protein structures in docking calculations for hit discovery, the exploration of biochemical pathways and toxicity prediction of drug candidates. We describe the computational engineering work necessary to enable large ensemble docking campaigns on supercomputers. We show examples where ensemble-based docking has significantly increased the number and the diversity of validated drug candidates. Finally, we illustrate how ensemble-based docking can be extended beyond hit discovery and toward providing a structural basis for the prediction of metabolism and off-target binding relevant to pre-clinical and clinical trials. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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37. L-Arabinose Binding, Isomerization, and Epimerization by D-Xylose Isomerase: X-Ray/Neutron Crystallographic and Molecular Simulation Study.
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Langan, Paul, Sangha, Amandeep K., Wymore, Troy, Parks, Jerry M., Yang, Zamin Koo, Hanson, B. Leif, Fisher, Zoe, Mason, Sax A., Blakeley, Matthew P., Forsyth, V. Trevor, Glusker, Jenny P., Carrell, Horace L., Smith, Jeremy C., Keen, David A., Graham, David E., and Kovalevsky, Andrey
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ARABINOSE , *CARRIER proteins , *ISOMERIZATION , *EPIMERIZATION , *CRYSTALLOGRAPHY , *MOLECULAR biology - Abstract
Summary D-xylose isomerase (XI) is capable of sugar isomerization and slow conversion of some monosaccharides into their C2-epimers. We present X-ray and neutron crystallographic studies to locate H and D atoms during the respective isomerization and epimerization of L-arabinose to L-ribulose and L-ribose, respectively. Neutron structures in complex with cyclic and linear L-arabinose have demonstrated that the mechanism of ring-opening is the same as for the reaction with D-xylose. Structural evidence and QM/MM calculations show that in the reactive Michaelis complex L-arabinose is distorted to the high-energy 5 S 1 conformation; this may explain the apparent high K M for this sugar. MD-FEP simulations indicate that amino acid substitutions in a hydrophobic pocket near C5 of L-arabinose can enhance sugar binding. L-ribulose and L-ribose were found in furanose forms when bound to XI. We propose that these complexes containing Ni 2+ cofactors are Michaelis-like and the isomerization between these two sugars proceeds via a cis -ene-diol mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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38. Supplemental Data Small Angle Neutron Scattering Reveals pH-dependent Conformational Changes in Trichoderma reesei Cellobiohydrolase I: IMPLICATIONS FOR ENZYMATIC ACTIVITY.
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Pingali, Sai Venkatesh, O'Neill, Hugh M., McGaughey, Joseph, Urban, Volker S., Rempe, Caroline S., Petridis, Loukas, Smith, Jeremy C., Evans, Barbara R., and Heller, William T.
- Subjects
- *
CELLULOSE 1,4-beta-cellobiosidase , *TRICHODERMA reesei , *BIOMASS , *POLYPEPTIDES , *CONFORMATIONAL analysis - Abstract
Cellobiohydrolase I (Cel7A) of the fungus Trichoderma reesei (now classified as an anamorph of Hypocrea jecorina) hydrolyzes crystalline cellulose to soluble sugars, making it of key interest for producing fermentable sugars from biomass for biofuel production. The activity of the enzyme is pH-dependent, with its highest activity occurring at pH 4-5. To probe the response of the solution structure of Cel7A to changes in pH, we measured small angle neutron scattering of it in a series of solutions having pH values of 7.0, 6.0, 5.3, and 4.2. As the pH decreases from 7.0 to 5.3, the enzyme structure remains well defined, possessing a spatial differentiation between the cellulose binding domain and the catalytic core that only changes subtly. At pH 4.2, the solution conformation of the enzyme changes to a structure that is intermediate between a properly folded enzyme and a denatured, unfolded state, yet the secondary structure of the enzyme is essentially unaltered. The results indicate that at the pH of optimal activity, the catalytic core of the enzyme adopts a structure in which the compact packing typical of a fully folded polypeptide chain is disrupted and suggest that the increased range of structures afforded by this disordered state plays an important role in the increased activity of Cel7A through conformational selection. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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- View/download PDF
39. Enzyme hydration, activity and flexibility: A neutron scattering approach
- Author
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Kurkal-Siebert, Vandana, Daniel, R.M., Finney, John L., Tehei, M., Dunn, R.V., and Smith, Jeremy C.
- Subjects
- *
ENZYMES , *NEUTRON diffraction , *DIFFRACTIVE scattering , *PROTEINS - Abstract
Abstract: Recent measurements have demonstrated enzyme activity at hydrations as low as 3%. The question of whether the hydration-induced enzyme flexibility is important for activity is addressed by performing picosecond dynamic neutron scattering experiments on pig liver esterase powders at various temperatures as well as solutions. At all temperatures and hydrations investigated here, significant quasielastic scattering intensity is found in the protein, indicating the presence of anharmonic, diffusive motion. As the hydration increases a temperature-dependent dynamical transition appears and strengthens involving additional diffusive motion. At low temperature, increasing hydration resulted in lower flexibility of the enzyme. At higher temperatures, systems containing sufficient number of water molecules interacting with the protein exhibit increased flexibility. The implication of these results is that, although the additional hydration-induced diffusive motion and flexibility at high temperatures in the enzyme detected here may be related to increased activity, they are not required for the enzyme to function. [Copyright &y& Elsevier]
- Published
- 2006
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40. Structural Basis of Cellulosome Efficiency Explored by Small Angle X-ray Scattering.
- Author
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Hammel, Michal, Fierobe, Henri-Pierre, Czjzek, Mirjam, Kurkal, Vandana, Smith, Jeremy C., Bayer, Edward A., Finet, Stéphanie, and Receveur-Bréchot, Véronique
- Subjects
- *
POLYMERS , *ULTRASTRUCTURE of plant cell walls , *PLANT ultrastructure , *PLANT cell walls , *EXTRACELLULAR enzymes , *PLANT cells & tissues , *MOLECULAR dynamics , *X-ray scattering - Abstract
Cellulose, the main structural component of plant cell walls, is the most abundant carbohydrate polymer in nature. To break down plant cell walls, anaerobic microorganisms have evolved a large extracellular enzyme complex termed cellulosome. This megadalton catalytic machinery organizes an enzymatic assembly, tenaciously bound to a scaffolding protein via specialized intermodular ‘cohesin-dockerin’ interactions that serve to enhance synergistic activity among the different catalytic subunits. Here, we report the solution structure properties of cellulosome-like assemblies analyzed by small angle x-ray scattering and molecular dynamics. The atomic models, generated by our strategy for the free chimeric scaffoldin and for binary and ternary complexes, reveal the existence of various conformations due to intrinsic structural flexibility with no, or only coincidental, inter-cohesin interactions. These results provide primary evidence concerning the mechanisms by which these protein assemblies attain their remarkable synergy. The data suggest that the motional freedom of the scaffoldin allows precise positioning of the complexed enzymes according to the topography of the substrate, whereas short-scale motions permitted by residual flexibility of the enzyme linkers allow ‘fine-tuning’ of individual catalytic domains. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
41. Density functional theory analysis of dimethylphosphate hydrolysis: effect of solvation and nucleophile variation
- Author
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Imhof, Petra, Fischer, Stefan, Krämer, Roland, and Smith, Jeremy C.
- Subjects
- *
DENSITY functionals , *SOLUTION (Chemistry) , *VACUUM , *FUNCTIONAL analysis - Abstract
Abstract: We model the hydrolytic cleavage of dimethylphosphate by hydroxide ion and water in the gas phase and in implicit water using density functional theory. In all cases the rate-determining step is the nucleophilic attack. The barrier for this nucleophilic attack in vacuum is much larger for the hydroxide than for the neutral nucleophile. However, in water the barriers are similar. The rate-determining step in the attack by the neutral nucleophile involves the concerted transfer of a proton from the water molecule to the phosphate ion and the formation of the P–O bond. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
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42. Mechanism of Primary Proton Transfer in Bacteriorhodopsin
- Author
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Bondar, Ana-Nicoleta, Elstner, Marcus, Suhai, Sándor, Smith, Jeremy C., and Fischer, Stefan
- Subjects
- *
BACTERIORHODOPSIN , *PROTON transfer reactions , *BACTERIAL pigments , *CHARGE transfer - Abstract
Recent structures of putative intermediates in the bacteriorhodopsin photocycle have provided valuable snapshots of the mechanism by which protons are pumped across the membrane. However, key steps remain highly controversial, particularly the proton transfer occurring immediately after retinal trans→cis photoisomerization. The gradual release of stored energy is inherently nonequilibrium: which photocycle intermediates are populated depends not only on their energy but also on their interconversion rates. To understand why the photocycle follows a productive (i.e., pumping), rather than some unproductive, relaxation pathway, it is necessary to know the relative energy barriers of individual steps. To discriminate between the many proposed scenarios of this process, we computed all its possible minimum-energy paths. This reveals that not one, but three very different pathways have energy barriers consistent with experiment. This result reconciles the conflicting views held on the mechanism and suggests a strategy by which the protein renders this essential step resilient. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
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43. The carboxylation status of osteocalcin has important consequences for its structure and dynamics.
- Author
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Kapoor, Karan, Pi, Min, Nishimoto, Satoru Kenneth, Quarles, Leigh Darryl, Baudry, Jerome, and Smith, Jeremy C.
- Subjects
- *
OSTEOCALCIN , *CALCIUM ions , *CARBOXYLATION , *RADIAL distribution function , *TERTIARY structure , *MOLECULAR dynamics - Abstract
The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism and expenditure. In this study, the role of γ-carboxylation of the glutamate residues in the structure-dynamics-function relationship in Ocn is investigated. Three forms of Ocn, differentially carboxylated at the Glu-17, 21 and 24 residues, along with a mutated form of Ocn carrying Glu/Ala mutations, are modeled and simulated using molecular dynamics (MD) simulation in the presence of calcium ions. Characterization of the global conformational dynamics of Ocn, described in terms of the orientational variations within its 3-helical domain, highlights large structural variations in the non-carboxylated osteocalcin (nOcn). The bi-carboxylated Ocn (bOcn) and tri-carboxylated (tOcn) species, in contrast, display relatively rigid tertiary structures, with the dynamics of most regions strongly correlated. Radial distribution functions calculated for both bOcn and tOcn show long-range ordering of the calcium ion distribution around the carboxylated glutamate (γGlu) residues, likely playing an important role in promoting stability of these Ocns. Additionally, the same calcium ions are observed to coordinate with neighboring γGlu, better shielding their negative charges and in turn stabilizing these systems more than do the singly coordinating calcium ions observed in the case of nOcn. bOcn is also found to exhibit a more helical C-terminal structure, that has been shown to activate its cellular receptor GPRC6A, highlighting the allosteric role of Ocn carboxylation in modulating the stability and binding potential of the active C-terminal. The carboxylation status of Ocn as well and its calcium coordination appear to have a direct influence on Ocn structure and dynamics, possibly leading to the known differences in Ocn biological function. Modification of Ocn sequence or its carboxylation state may provide the blueprint for developing high-affinity peptides targeting its cellular receptor GPRC6A, with therapeutic potential for treatment of metabolic disorders. • Osteocalcin (Ocn) plays important structural and endocrine functions. • MD simulations of different carboxylated forms of Ocn carried out in presence of calcium ions. • Calcium ions actively shield neighboring negative charges in carboxylated Ocn, promoting stability. • Compact tri-carboxylated Ocn may promote configuration in extracellular matrix. • Dynamic nature of undecarboxylated Ocns may promote hormonal function. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
44. Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold.
- Author
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Green, Adam T., Moniruzzaman, Mohammad, Cooper, Connor J., Walker, John K., Smith, Jeremy C., Parks, Jerry M., and Zgurskaya, Helen I.
- Subjects
- *
CHEMICAL inhibitors , *DRUG resistance in bacteria , *BINDING site assay , *CHIMERIC proteins , *MEMBRANE proteins - Abstract
Multidrug efflux is a major contributor to antibiotic resistance in Gram-negative bacterial pathogens. Inhibition of multidrug efflux pumps is a promising approach for reviving the efficacy of existing antibiotics. Previously, inhibitors targeting both the efflux transporter AcrB and the membrane fusion protein AcrA in the Escherichia coli AcrAB-TolC efflux pump were identified. Here we use existing physicochemical property guidelines to generate a filtered library of compounds for computational docking. We then experimentally test the top candidate coumpounds using in vitro binding assays and in vivo potentiation assays in bacterial strains with controllable permeability barriers. We thus identify a new class of inhibitors of E. coli AcrAB-TolC. Six molecules with a shared scaffold were found to potentiate the antimicrobial activity of erythromycin and novobiocin in hyperporinated E. coli cells. Importantly, these six molecules were also active in wild-type strains of both Acinetobacter baumannii and Klebsiella pneumoniae , potentiating the activity of erythromycin and novobiocin up to 8-fold. • Generated a focused library of compounds with specific physicochemical properties. • Performed ensemble docking of compounds to multiple sites on AcrA. • Measured in vivo activity of top compounds from docking. • Identified six molecules with a shared scaffold that potentiate antibiotic activity. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
45. Prediction of peptide binding to MHC using machine learning with sequence and structure-based feature sets.
- Author
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Aranha, Michelle P., Spooner, Catherine, Demerdash, Omar, Czejdo, Bogdan, Smith, Jeremy C., and Mitchell, Julie C.
- Subjects
- *
DESCRIPTOR systems , *MACHINE learning , *MAJOR histocompatibility complex , *AMINO acid sequence , *SUPPORT vector machines - Abstract
Selecting peptides that bind strongly to the major histocompatibility complex (MHC) for inclusion in a vaccine has therapeutic potential for infections and tumors. Machine learning models trained on sequence data exist for peptide:MHC (p:MHC) binding predictions. Here, we train support vector machine classifier (SVMC) models on physicochemical sequence-based and structure-based descriptor sets to predict peptide binding to a well-studied model mouse MHC I allele, H-2Db. Recursive feature elimination and two-way forward feature selection were also performed. Although low on sensitivity compared to the current state-of-the-art algorithms, models based on physicochemical descriptor sets achieve specificity and precision comparable to the most popular sequence-based algorithms. The best-performing model is a hybrid descriptor set containing both sequence-based and structure-based descriptors. Interestingly, close to half of the physicochemical sequence-based descriptors remaining in the hybrid model were properties of the anchor positions, residues 5 and 9 in the peptide sequence. In contrast, residues flanking position 5 make little to no residue-specific contribution to the binding affinity prediction. The results suggest that machine-learned models incorporating both sequence-based descriptors and structural data may provide information on specific physicochemical properties determining binding affinities. • Sequence-based physicochemical descriptor sets were benchmarked for predicting peptide binding to mouse MHC I allele, H-2Db. • Improvement in binding prediction was obtained by combining the best performing sequence-based features with structure-based features. • Features of the residues at anchor sites, 5 and 9 greatly influence peptide binding prediction. • Residues at positions 4 and 6 flanking the anchor residue made little to no contribution to the binding affinity prediction of the model. • The machine learning method described here can be useful in filtering samples with large number of potential binders. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
46. "To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation.
- Author
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Kovalevsky, Andrey, Aggarwal, Mayank, Velazquez, Hector, Cuneo, Matthew J., Blakeley, Matthew P., Weiss, Kevin L., Smith, Jeremy C., Fisher, S. Zoë, and McKenna, Robert
- Subjects
- *
CRYSTALLOGRAPHY , *CONDENSED matter physics , *RADIOACTIVE substances , *HYDROGEN analysis , *ATOMIC physics - Abstract
Summary Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
47. Preface
- Author
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Pettitt, B.Montgomery and Smith, Jeremy C.
- Published
- 1995
- Full Text
- View/download PDF
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