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The calibration of torsional interaction terms by fitting relative gas‐phase conformational energies against their quantum‐mechanical values is a common procedure in force‐field development. However, much less attention has been paid to the optimization of third‐neighbor nonbonded interaction parameters, despite their strong coupling with the torsions. This article introduces an algorithm termed LLS‐SC, aimed at simultaneously parametrizing torsional and third‐neighbor interaction terms based on relative conformational energies. It relies on a self‐consistent (SC) procedure where each iteration involves a linear least‐squares (LLS) regression followed by a geometry optimization of the reference structures. As a proof‐of‐principle, this method is applied to obtain torsional and third‐neighbor interaction parameters for aliphatic chains in the context of the GROMOS 53A6 united‐atom force field. The optimized parameter set is compared to the original one, which has been fitted manually against thermodynamic properties for small linear alkanes. The LLS‐SC implementation is freely available under http://github.com/mssm-labmmol/profiler. [ABSTRACT FROM AUTHOR]

Docking studies play a critical role in the current workflow of drug discovery. However, limitations may often arise through factors including inadequate ligand sampling, a lack of protein flexibility, scoring function inadequacies (e.g., due to metals, co‐factors, etc.), and difficulty in retaining explicit water molecules. Herein, we present a novel CHARMM‐based induced fit docking (CIFDock) workflow that can circumvent these limitations by employing all‐atom force fields coupled to enhanced sampling molecular dynamics procedures. Self‐guided Langevin dynamics simulations are used to effectively sample relevant ligand conformations, side chain orientations, crystal water positions, and active site residue motion. Protein flexibility is further enhanced by dynamic sampling of side chain orientations using an expandable rotamer library. Steps in the procedure consisting of fixing individual components (e.g., the ligand) while sampling the other components (e.g., the residues in the active site of the protein) allow for the complex to adapt to conformational changes. Ultimately, all components of the complex—the protein, ligand, and waters—are sampled simultaneously and unrestrained with SGLD to capture any induced fit effects. This modular flexible docking procedure is automated using CHARMM scripting, interfaced with SLURM array processing, and parallelized to use the desired number of processors. We validated the CIFDock procedure by performing cross‐docking studies using a data set comprised of 21 pharmaceutically relevant proteins. Five variants of the CHARMM‐based SWISSDOCK scoring functions were created to quantify the results of the final generated poses. Results obtained were comparable to, or in some cases improved upon, commercial docking program data. [ABSTRACT FROM AUTHOR]

FFLUX is a biomolecular force field under construction, based on Quantum Chemical Topology (QCT) and machine learning (kriging), with a minimalistic and physically motivated design. A detailed analysis of the forces within the kriging models as treated in FFLUX is presented, taking as a test example a liquid water model. The energies of topological atoms are modeled as 3Natoms‐6 dimensional potential energy surfaces, using atomic local frames to represent the internal degrees of freedom. As a result, the forces within the kriging models in FFLUX are inherently N‐body in nature where N refers to Natoms. This provides a fuller picture that is closer to a true quantum mechanical representation of interactions between atoms. The presented computational example quantitatively showcases the non‐negligible (as much as 9%) three‐body nature of bonded forces and angular forces in a water molecule. We discuss the practical impact on the pressure calculation with N‐body forces and periodic boundary conditions (PBC) in molecular dynamics, as opposed to classical force fields with two‐body forces. The equivalence between the PBC‐related correction terms in the general virial equation is shown mathematically. [ABSTRACT FROM AUTHOR]

Flavin containing molecules form a group of important cofactors that assist a wide range of enzymatic reactions. Flavins use the redox‐active isoalloxazine system, which is capable of one‐ and two‐electron transfer reactions and can exist in several protonation states. In this work, molecular mechanics force field parameters compatible with the CHARMM36 all‐atom additive force field were derived for biologically important flavins, including riboflavin, flavin mononucleotide, and flavin adenine dinucleotide. The model was developed for important protonation and redox states of the isoalloxazine group. The partial charges were derived using the CHARMM force field parametrization strategy, where quantum mechanics water–solute interactions are used to target optimization. In addition to monohydrate energies and geometries, electrostatic potential around the compound was used to provide additional restraints during the charge optimization. Taking into account the importance of flavin‐containing molecules special attention was given to the quality of bonded terms. All bonded terms, including stiff terms and torsion angle parameters, were parametrized using exhaustive potential energy surface scans. In particular, the model reproduces well the butterfly motion of isoalloxazine in the oxidized and reduced forms as predicted by quantum mechanics in gas phase. The model quality is illustrated by simulations of four flavoproteins. Overall, the presented molecular mechanics model will be of utility to model flavin cofactors in different redox states. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The parametrization of classical nonbonded models of metal ions has been widely addressed in the recent years. Despite the continuous development of novel and more physically inspired functional forms, the 12‐6 Lennard‐Jones plus Coulomb potential is still the most adopted force field in molecular dynamics (MD) codes, owing to its simple form and easy implementation. However, due to the integer formal charge, unpolarizable force fields of ions may suffer from overestimated interatomic electrostatic interactions, leading to nonphysical clustering or repulsion between such full charges. The electronic continuum correction (ECC) can fix this problem through a simple inclusion of solvent polarization effects via ionic charge rescaling. In this work, the development of novel nonbonded models for mono, divalent, and highly charged metal ions is presented. For each metal species, the ionic charge has been scaled, according to the ECC. Lennard‐Jones parameters have been optimized using experimental structural and thermodynamic properties as target quantities. Performances of the proposed models are discussed and compared with the literature data, while transferability attitudes among different and well‐known water models are evaluated. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The topmost polyamide (PA) layer of the thin‐film‐composite reverse osmosis (RO) membrane is the most important part in the membrane‐based RO technology. With the aid of molecular dynamics simulations, many PA layer‐related features in the RO process can be revealed. With many novel types of PA RO membranes out of trimesoyl chloride/m‐phenylenediamine monomers developed in the laboratory, a convenient model building tool for these PA layer systems is urgently needed to conduct the theoretical analysis. Here, we develop a new universal toolkit for constructing PA RO membranes, named as MembrFactory, which combines flexibility of force fields and membrane compositions. A key characteristic of our approach is the use of monomers as the starting state, and the final membrane model was obtained automatically by stepwise reaction between the functional groups on the monomers. The reliability of MembrFactory has been validated by constructing several common PA RO membranes. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We propose a general strategy to remediate force‐field artifacts in describing pairwise interactions among similar molecules M in the vicinity of another chemical species, C, like water molecules interacting at short distance from a monoatomic ion. This strategy is based on introducing a three‐body potential energy term that alters the pairwise interactions among M‐type molecules when they lie at short range from the species C. In other words the species C is the center of a space domain where the pairwise interactions among the molecules M is altered. Here, we apply it to improve the description of the water interactions provided by the polarizable water model TCPE/2013 in the vicinity of halides, from F− to At−, and of the prototypical carboxylate anion CH3COO−. We show the accuracy and the transferability of such an approach to investigate not only the hydration process of single anions but also of a salt solution NH4+/Cl‐ in aqueous phase. This strategy can be used to remediate the drawbacks of any kind of force fields. © 2019 Wiley Periodicals, Inc. A general strategy is proposed to remediate force‐field artifacts in describing solvent pairwise interactions in the vicinity of a solute, based on introducing a three‐body potential energy term that alters the solvent pairwise interactions in a space domain centered at the solute. It is used to improve the description of the water interactions provided by the polarizable water model TCPE/2013 in the vicinity of halides, from F− to At−, and of the carboxylate anion CH3COO−. [ABSTRACT FROM AUTHOR]

We re-investigate the image charge model of Iori and Corni (Iori and Corni, J. Comput. Chem. 2008, 29, 1656). We find that a simple symmetrization of their model allows to obtain quantitatively correct results for the electrostatic interaction of a water molecule with a metallic surface. This symmetrization reduces the magnitude of the electrostatic interaction to less than 10% of the total interaction energy. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

An accurate van der Waals force field (VDW FF) was derived from highly precise quantum mechanical (QM) calculations. Small molecular clusters were used to explore van der Waals interactions between gas molecules and porous materials. The parameters of the accurate van der Waals force field were determined by QM calculations. To validate the force field, the prediction results from the VDW FF were compared with standard FFs, such as UFF, Dreiding, Pcff, and Compass. The results from the VDW FF were in excellent agreement with the experimental measurements. This force field can be applied to the prediction of the gas density (H2, CO2, C2H4, CH4, N2, O2) and adsorption performance inside porous materials, such as covalent organic frameworks (COFs), zeolites and metal organic frameworks (MOFs), consisting of H, B, N, C, O, S, Si, Al, Zn, Mg, Ni, and Co. This work provides a solid basis for studying gas adsorption in porous materials. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Conventional classical force fields by construction do not explicitly partition intermolecular interactions to include polarization and charge transfer effects, whereas fully quantum mechanical treatments allow a means to effect this dissection (although not uniquely due to the lack of a charge transfer operator). Considering the importance of polarization in a variety of systems, a particular class of classical models, charge equilibration models, have been extensively developed to study those systems; since these types of interaction models are inherently based on movement of charge throughout a system, they are natural platform for including polarization and charge transfer effects within the context of molecular simulations. Here, we present two bond-space charge equilibration models we term as QE2 and mixed QE2 treat charge transfer in classical molecular mechanical calculations those provide practical solutions to two major drawbacks of charge equilibration models: (a) a nonvanishing amount of charge transfer between two heteroatoms at large separations, and (b) superlinear polarizability scaling during bond dissociation due to charge transfer over unphysical, large distances. To control charge transfer during dissociation of a bond in a molecular system, we introduce a distance-dependent scaling function (QE2 model) which, controls and recovers physical behavior of the homonuclear and heteronuclear charge transfer between two atoms at small and large values of internuclear separation; and the mixed QE2 model in which we combine the QE2 model under allow and disallow charge transfer situations that describe both charge transfer and polarizability in a distance-dependent manner. We demonstrate the utility of both models in the case of a water dimer, and compare the results with other existing models, and further, we perform short molecular dynamics simulations for few water clusters with the QE2 model to show the charge transfer and internuclear separation are correlated in dynamics. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The fully polarizable, multipolar, and atomistic force field protein FFLUX is being built from machine learning (i.e., kriging) models, each of which predicts an atomic property. Each atom of a given protein geometry needs to be assigned such a kriging model. Such a knowledgeable atom needs to be informed about a sufficiently large environment around it. The resulting complexity can be tackled by collecting the 20 natural amino acids into a few groups. Using substituted deca-alanines, we present the proof-of-concept that a given atom's charge can be modeled by a few kriging models only. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The force field conversion from one MD program to another one is exhausting and error-prone. Although single conversion tools from one MD program to another exist not every combination and both directions of conversion are available for the favorite MD programs A mber, C harmm, D l-P oly, G romacs, and L ammps. We present here a general tool for the force field conversion on the basis of an XML document. The force field is converted to and from this XML structure facilitating the implementation of new MD programs for the conversion. Furthermore, the XML structure is human readable and can be manipulated before continuing the conversion. We report, as testcases, the conversions of topologies for acetonitrile, dimethylformamide, and 1-ethyl-3-methylimidazolium trifluoromethanesulfonate comprising also Urey-Bradley and Ryckaert-Bellemans potentials. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We present a systematic test of the performance of three popular united-atom force fields-OPLS-UA, GROMOS and TraPPE-at predicting hydrophobic solvation, more precisely at describing the solvation of alkanes in alkanes. Gibbs free energies of solvation were calculated for 52 solute/solvent pairs from Molecular Dynamics simulations and thermodynamic integration making use of the IBERCIVIS volunteer computing platform. Our results show that all force fields yield good predictions when both solute and solvent are small linear or branched alkanes (up to pentane). However, as the size of the alkanes increases, all models tend to increasingly deviate from experimental data in a systematic fashion. Furthermore, our results confirm that specific interaction parameters for cyclic alkanes in the united-atom representation are required to account for the additional excluded volume within the ring. Overall, the TraPPE model performs best for all alkanes, but systematically underpredicts the magnitude of solvation free energies by about 6% (RMSD of 1.2 kJ/mol). Conversely, both GROMOS and OPLS-UA systematically overpredict solvation free energies (by ∼13% and 15%, respectively). The systematic trends suggest that all models can be improved by a slight adjustment of their Lennard-Jones parameters. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

New equations for torque and atomic force are derived for use in flexible molecule force fields with atomic multipoles. The expressions are based on Cartesian tensors with arbitrary multipole rank. The standard method for rotating Cartesian tensor multipoles and calculating torque is to first represent the tensor with n indexes and 3 n redundant components. In this work, new expressions for directly rotating the unique ( n + 1)( n + 2)/2 Cartesian tensor multipole components Θ pqr are given by introducing Cartesian tensor rotation matrix elements X( R). A polynomial expression and a recursion relation for X( R) are derived. For comparison, the analogous rotation matrix for spherical tensor multipoles are the Wigner functions D( R). The expressions for X( R) are used to derive simple equations for torque and atomic force. The torque and atomic force equations are applied to the geometry optimization of small molecule crystal unit cells. In addition, a discussion of computational efficiency as a function of increasing multipole rank is given for Cartesian tensors. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Computational protein design depends on an energy function and an algorithm to search the sequence/conformation space. We compare three stochastic search algorithms: a heuristic, Monte Carlo (MC), and a Replica Exchange Monte Carlo method (REMC). The heuristic performs a steepest-descent minimization starting from thousands of random starting points. The methods are applied to nine test proteins from three structural families, with a fixed backbone structure, a molecular mechanics energy function, and with 1, 5, 10, 20, 30, or all amino acids allowed to mutate. Results are compared to an exact, 'Cost Function Network' method that identifies the global minimum energy conformation (GMEC) in favorable cases. The designed sequences accurately reproduce experimental sequences in the hydrophobic core. The heuristic and REMC agree closely and reproduce the GMEC when it is known, with a few exceptions. Plain MC performs well for most cases, occasionally departing from the GMEC by 3-4 kcal/mol. With REMC, the diversity of the sequences sampled agrees with exact enumeration where the latter is possible: up to 2 kcal/mol above the GMEC. Beyond, room temperature replicas sample sequences up to 10 kcal/mol above the GMEC, providing thermal averages and a solution to the inverse protein folding problem. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The currently available force field parameters for modified RNA residues in AMBER show significant deviations in conformational properties from experimental observations. The examination of the transferability of the recently revised torsion parameters revealed that there was an overall improvement in the conformational properties for some of the modifications but the improvements were still insufficient in describing the sugar pucker preferences ( J. Chem. Inf. Model. 2014, 54, 1129-1142). Here, we report an approach for the development and fine tuning of the AMBER force field parameters for 2-thiouridine, 4-thiouridine, and pseudouridine with diverse conformational preferences. The χ torsion parameters were reparameterized at the individual nucleoside level. The effect of combining the revised γ torsion parameter and modifying the Lennard-Jones σ parameters were also tested by directly comparing the conformational preferences obtained from our extensive molecular dynamics simulations with those from experimental observations. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Carotenoids are important actors both in light-harvesting (LH) and in photoprotection functions of photosynthetic pigment-protein complexes. A deep theoretical investigation of this multiple role is still missing owing to the difficulty of describing the delicate interplay between electronic and nuclear degrees of freedom. A possible strategy is to combine accurate quantum mechanical (QM) methods with classical molecular dynamics. To do this, however, accurate force-fields (FF) are necessary. This article presents a new FF for the different carotenoids present in LH complexes of plants. The results show that all the important structural properties described by the new FF are in very good agreement with QM reference values. This increased accuracy in the simulation of the structural fluctuations is also reflected in the description of excited states. Both the energy order and the different nature of the lowest singlet states are preserved during the dynamics when the new FF is used, whereas an unphysical mixing is found when a standard FF is used. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We introduce a simple but computationally very efficient harmonic force field, which works for all fullerene structures and includes bond stretching, bending, and torsional motions as implemented into our open-source code Fullerene. This gives accurate geometries and reasonably accurate vibrational frequencies with root mean square deviations of up to 0.05 Å for bond distances and 45.5 cm−1 for vibrational frequencies compared with more elaborate density functional calculations. The structures obtained were used for density functional calculations of Goldberg-Coxeter fullerenes up to C980. This gives a rather large range of fullerenes making it possible to extrapolate to the graphene limit. Periodic boundary condition calculations using density functional theory (DFT) within the projector augmented wave method gave an energy difference between −8.6 and −8.8 kcal/mol at various levels of DFT for the reaction C60→graphene (per carbon atom) in excellent agreement with the linear extrapolation to the graphene limit (−8.6 kcal/mol at the Perdew-Burke-Ernzerhof level of theory). © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In this article, we present a Python-based library of high quality semi-global potential energy surfaces for 50 polyatomic molecules with up to six atoms. We anticipate that these surfaces will find widespread application in the testing of new potential energy surface construction algorithms and nuclear ro-vibrational structure theories. To this end, we provide the ability to generate the energy derivatives required for Taylor series expansions to sixth order about any point on the potential energy surface in a range of common coordinate systems, including curvilinear internal, Cartesian, and normal mode coordinates. The PyPES package, along with FORTRAN, C, MATLAB and Mathematica wrappers, is available at . © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We present an efficient scheme for parametrizing complex molecule-surface force fields from ab initio data. The cost of producing a sufficient fitting library is mitigated using a 2D periodic embedded slab model made possible by the quantum mechanics/molecular mechanics scheme in CP2K. These results were then used in conjunction with genetic algorithm (GA) methods to optimize the large parameter sets needed to describe such systems. The derived potentials are able to well reproduce adsorption geometries and adsorption energies calculated using density functional theory. Finally, we discuss the challenges in creating a sufficient fitting library, determining whether or not the GA optimization has completed, and the transferability of such force fields to similar molecules. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We comprehensively illustrate a general process of fitting allatom molecular mechanics force field (FF) parameters based on quantum mechanical calculations and experimental thermodynamic data. For common organic molecules with free dihedral rotations, this FF format is comprised of the usual bond stretching, angle bending, proper and improper dihedral rotation, and 1-4 scaling pair interactions. An extra format of 1-n scaling pair interaction is introduced when a specific intramolecular rotation is strongly hindered. We detail how the preferred order of fitting all intramolecular FF parameters can be determined by systematically generating characteristic configurations. The intermolecular Van der Waals parameters are initially taken from the literature data but adjusted to obtain a better agreement between the molecular dynamics (MD) simulation results and the experimental observations if necessary. By randomly choosing the molecular configurations from MD simulation and comparing their energies computed from FF parameters and quantum mechanics, the FF parameters can be verified self-consistently. Using an example of a platform chemical 3-hydroxypropionic acid, we detail the comparison between the new fitting parameters and the existing FF parameters. In particular, the introduced systematic approach has been applied to obtain the dihedral angle potential and 1-n scaling pair interaction parameters for 48 organic molecules with different functionality. We suggest that this procedure might be used to obtain better dihedral and 1-n interaction potentials when they are not available in the current widely used FF. [ABSTRACT FROM AUTHOR]

An extension of the GROMOS 53A6GLYC force field for carbohydrates to encompass glycoprotein linkages is presented. The set includes new atomic charges and incorporates adequate torsional potential parameters for N-, S-, C-, P-, and O-glycosydic linkages, offering compatibility with the GROMOS force field family for proteins. Validation included the description of glycosydic linkage geometries between amino acid and monosaccharide residues, comparison of NMR-derived protein-carbohydrate and carbohydrate-carbohydrate nuclear overhauser effect (NOE) signals for glycoproteins and the effects of glycosylation on protein flexibility and dynamics. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The reliability of the linear interaction energy (LIE) depends on the atomic charge model used to delineate the Coulomb interaction between the ligand and its environment. In this work, the polarized protein-specific charge (PPC) implementing a recently proposed fitting scheme has been examined in the LIE calculations of the binding affinities for avidin and β-secretase binding complexes. This charge fitting scheme, termed delta restrained electrostatic potential, bypasses the prevalent numerical difficulty of rank deficiency in electrostatic-potential-based charge fitting methods via a dual-step fitting strategy. A remarkable consistency between the predicted binding affinities and the experimental measurement has been observed. This work serves as a direct evidence of PPC's applicability in rational drug design. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We present Hydrogen Dynamics (HYDYN), a method that allows explicit proton transfer in classical force field molecular dynamics simulations at thermodynamic equilibrium. HYDYN reproduces the characteristic properties of the excess proton in water, from the special pair dance, to the continuous fluctuation between the limiting Eigen and Zundel complexes, and the water reorientation beyond the first solvation layer. Advantages of HYDYN with respect to existing methods are computational efficiency, microscopic reversibility, and easy parameterization for any force field. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The anisotropic effects and short-range quantum effects are essential characters in the formation of halogen bonds. Since there are an array of applications of halogen bonds and much difficulty in modeling them in classical force fields, the current research reports solely the polarizable ellipsoidal force field (PEff) for halogen bonds. The anisotropic charge distribution was represented with the combination of a negative charged sphere and a positively charged ellipsoid. The polarization energy was incorporated by the induced dipole model. The resulting force field is 'physically motivated,' which includes separate, explicit terms to account for the electrostatic, repulsion/dispersion, and polarization interaction. Furthermore, it is largely compatible with existing, standard simulation packages. The fitted parameters are transferable and compatible with the general AMBER force field. This PEff model could correctly reproduces the potential energy surface of halogen bonds at MP2 level. Finally, the prediction of the halogen bond properties of human Cathepsin L (hcatL) has been found to be in excellent qualitative agreement with the cocrystal structures. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A classical molecular mechanics force field, able to simulate coordination polymers (CP) based on ruthenium carboxylates (Ru2(O2CReq)4Lax) (eq = equatorial group containing aliphatic chains, Lax= axial ligand), has been developed. New parameters extracted from experimental data and quantum calculations on short aliphatic chains model systems were included in the generalized AMBER force field. The proposed parametrization was evaluated using model systems with known structure, containing either short or long aliphatic chains; experimental results were reproduced satisfactorily. This modified force field, although in a preliminary stage, could then be applied to long chain liquid crystalline compounds. The resulting atomistic simulations allowed assessing the relative influence of the factors determining the CP conformation, determinant for the physical properties of these materials. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In force field parameter development using ab initio potential energy surfaces (PES) as target data, an important but often neglected matter is the lack of a weighting scheme with optimal discrimination power to fit the target data. Here, we developed a novel partition function-based weighting scheme, which not only fits the target potential energies exponentially like the general Boltzmann weighting method, but also reduces the effect of fitting errors leading to overfitting. The van der Waals (vdW) parameters of benzene and propane were reparameterized by using the new weighting scheme to fit the high-level ab initio PESs probed by a water molecule in global configurational space. The molecular simulation results indicate that the newly derived parameters are capable of reproducing experimental properties in a broader range of temperatures, which supports the partition function-based weighting scheme. Our simulation results also suggest that structural properties are more sensitive to vdW parameters than partial atomic charge parameters in these systems although the electrostatic interactions are still important in energetic properties. As no prerequisite conditions are required, the partition function-based weighting method may be applied in developing any types of force field parameters. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Parameterization of a molecular dynamics force field is essential in realistically modeling the physicochemical processes involved in a molecular system. This step is often challenging when the equations involved in describing the force field are complicated as well as when the parameters are mostly empirical. ReaxFF is one such reactive force field which uses hundreds of parameters to describe the interactions between atoms. The optimization of the parameters in ReaxFF is done such that the properties predicted by ReaxFF matches with a set of quantum chemical or experimental data. Usually, the optimization of the parameters is done by an inefficient single-parameter parabolic-search algorithm. In this study, we use a robust metropolis Monte-Carlo algorithm with simulated annealing to search for the optimum parameters for the ReaxFF force field in a high-dimensional parameter space. The optimization is done against a set of quantum chemical data for MgSO4 hydrates. The optimized force field reproduced the chemical structures, the equations of state, and the water binding curves of MgSO4 hydrates. The transferability test of the ReaxFF force field shows the extend of transferability for a particular molecular system. This study points out that the ReaxFF force field is not indefinitely transferable. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The DNA binding domain of transposon Tn916 integrase (INT-DBD) binds to DNA target site by positioning the face of a three-stranded antiparallel β-sheet within the major groove. As the negatively charged DNA directly interacts with the positively charged residues (such as Arg and Lys) of INT-DBD, the electrostatic interaction is expected to play an important role in the dynamical stability of the protein-DNA binding complex. In the current work, the combined use of quantum-based polarized protein-specific charge (PPC) for protein and polarized nucleic acid-specific charge (PNC) for DNA were employed in molecular dynamics simulation to study the interaction dynamics between INT-DBD and DNA. Our study shows that the protein-DNA structure is stabilized by polarization and the calculated protein-DNA binding free energy is in good agreement with the experimental data. Furthermore, our study revealed a positive correlation between the measured binding energy difference in alanine mutation and the occupancy of the corresponding residue's hydrogen bond. This correlation relation directly relates the contribution of a specific residue to protein-DNA binding energy to the strength of the hydrogen bond formed between the specific residue and DNA. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Lysozyme is a well-studied enzyme that hydrolyzes the β-(1,4)-glycosidic linkage of N-acetyl-β-glucosamine (NAG) n oligomers. The active site of hen egg-white lysozyme (HEWL) is believed to consist of six subsites, A-F that can accommodate six sugar residues. We present studies exploring the use of polarizable force fields in conjunction with all-atom molecular dynamics (MD) simulations to analyze binding structures of complexes of lysozyme and NAG trisaccharide, (NAG)3. MD trajectories are applied to analyze structures and conformation of the complex as well as protein-ligand interactions, including the hydrogen-bonding network in the binding pocket. Two binding modes (ABC and BCD) of (NAG)3 are investigated independently based on a fixed-charge model and a polarizable model. We also apply molecular mechanics with generalized born and surface area (MM-GBSA) methods based on MD using both nonpolarizable and polarizable force fields to compute binding free energies. We also study the correlation between root-mean-squared deviation and binding free energies of the wildtype and W62Y mutant; we find that for this prototypical system, approaches using the MD trajectories coupled with implicit solvent models are equivalent for polarizable and fixed-charge models. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We present a set of force field (FF) parameters compatible with the AMBER03 FF to describe five cofactors in photosystem II (PSII) of oxygenic photosynthetic organisms: plastoquinone-9 (three redox forms), chlorophyll-a, pheophytin-a, heme-b, and β-carotene. The development of a reliable FF for these cofactors is an essential step for performing molecular dynamics simulations of PSII. Such simulations are important for the calculation of absorption spectrum and the further investigation of the electron and energy transfer processes. We have derived parameters for partial charges, bonds, angles, and dihedral-angles from solid theoretical models using systematic quantum mechanics (QM) calculations. We have shown that the developed FF parameters are in good agreement with both ab initio QM and experimental structural data in small molecule crystals as well as protein complexes. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Considering N-methylacetamide (NMA) as a model compound, new interaction parameters are developed for the amide function in the GROMOS force field that are compatible with the recently derived 53A6OXY parameter set for oxygen-containing chemical functions. The resulting set, referred to as 53A6OXY+A, represents an improvement over earlier GROMOS force-field versions in the context of the pure-liquid properties of NMA, including the density, heat of vaporization, dielectric permittivity, self-diffusion constant and viscosity, as well as in terms of the Gibbs hydration free energy of this molecule. Assuming that NMA represents an adequate model compound for the backbone of peptides, 53A6OXY+A may be expected to also provide an improved description of polypeptide chains. As an initial test, simulations are reported for two β-peptides characterized by very different folding properties in methanol. For these systems, earlier force-field versions provided good agreement with experimental NMR data, and the test shows that the improved description achieved in the context of NMA is not accompanied by any deterioration in the representation of the conformational properties of these peptides. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Recently, many polarizable force fields have been devised to describe induction effects between molecules. In popular polarizable models based on induced dipole moments, atomic polarizabilities are the essential parameters and should be derived carefully. Here, we present a parameterization scheme for atomic polarizabilities using a minimization target function containing both molecular and atomic information. The main idea is to adopt reference data only from quantum chemical calculations, to perform atomic polarizability parameterizations even when relevant experimental data are scarce as in the case of electronically excited molecules. Specifically, our scheme assigns the atomic polarizabilities of any given molecule in such a way that its molecular polarizability tensor is well reproduced. We show that our scheme successfully works for various molecules in mimicking dipole responses not only in ground states but also in valence excited states. The electrostatic potential around a molecule with an externally perturbing nearby charge also exhibits a near-quantitative agreement with the reference data from quantum chemical calculations. The limitation of the model with isotropic atoms is also discussed to examine the scope of its applicability. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Computer simulation using molecular dynamics is increasingly used to simulate the folding equilibria of peptides and small proteins. Yet, the quality of the obtained results depends largely on the quality of the force field used. This comprises the solute as well as the solvent model and their energetic and entropic compatibility. It is, however, computational very expensive to perform test simulations for each combination of force-field parameters. Here, we use the one-step perturbation technique to predict the change of the free enthalpy of folding of a β-peptide in methanol solution due to changing a variety of force-field parameters. The results show that changing the solute backbone partial charges affects the folding equilibrium, whereas this is relatively insensitive to changes in the force constants of the torsional energy terms of the force field. Extending the cut-off distance for nonbonded interactions beyond 1.4 nm does not affect the folding equilibrium. The same result is found for a change of the reaction-field permittivity for methanol from 17.7 to 30. The results are not sensitive to the criterion, e.g., atom-positional RMSD or number of hydrogen bonds, that is used to distinguish folded and unfolded conformations. Control simulations with perturbed Hamiltonians followed by backward one-step perturbation indicated that quite large perturbations still yield reliable results. Yet, perturbing all solvent molecules showed where the limitations of the one-step perturbation technique are met. The evaluated methodology constitutes an efficient tool in force-field development for molecular simulation by reducing the number of required separate simulations by orders of magnitude. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

We describe the development of force field parameters for methylated lysines and arginines, and acetylated lysine for the CHARMM all-atom force field. We also describe a CHARMM united-atom force field for modified sidechains suitable for use with fragment-based docking methods. The development of these parameters is based on results of ab initio quantum mechanics calculations of model compounds with subsequent refinement and validation by molecular mechanics and molecular dynamics simulations. The united-atom parameters are tested by fragment docking to target proteins using the MCSS procedure. The all-atom force field is validated by molecular dynamics simulations of multiple experimental structures. In both sets of calculations, the computational predictions using the force field were compared to the corresponding experimental structures. We show that the parameters yield an accurate reproduction of experimental structures. Together with the existing CHARMM force field, these parameters will enable the general modeling of post-translational modifications of histone tails. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

The ForceFit program package has been developed for fitting classical force field parameters based upon a force matching algorithm to quantum mechanical gradients of configurations that span the potential energy surface of the system. The program, which runs under UNIX and is written in C++, is an easy-to-use, nonproprietary platform that enables gradient fitting of a wide variety of functional force field forms to quantum mechanical information obtained from an array of common electronic structure codes. All aspects of the fitting process are run from a graphical user interface, from the parsing of quantum mechanical data, assembling of a potential energy surface database, setting the force field, and variables to be optimized, choosing a molecular mechanics code for comparison to the reference data, and finally, the initiation of a least squares minimization algorithm. Furthermore, the code is based on a modular templated code design that enables the facile addition of new functionality to the program. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

The structural and the dynamic features of the Calbindin (CaB) protein in its holo and apo states are compared using molecular dynamics simulations under nine different force fields (FFs) (G43a1, G53a6, Opls-AA, Amber94, Amber99, Amber99p, AmberGS, AmberGSs, and Amber99sb). The results show that most FFs reproduce reasonably well the majority of the experimentally derived features of the CaB protein. However, in several cases, there are significant differences in secondary structure properties, root mean square deviations (RMSDs), root mean square fluctuations (RMSFs), and S2 order parameters among the various FFs. What is more, in certain cases, these parameters differed from the experimentally derived values. Some of these deviations became noticeable only after 50 ns. A comparison with experimental data indicates that, for CaB, the Amber94 shows overall best agreement with the measured values, whereas several others seem to deviate from both crystal and nuclear magnetic resonance data. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

The AMBER and CHARMM force fields are analyzed from the viewpoint of the permutational symmetry of the potential for feasible exchanges of identical atoms and chemical groups in amino and nucleic acids. In each case, we propose schemes for symmetrizing the potentials, which greatly facilitate the bookkeeping associated with constructing kinetic transition networks via geometry optimization. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

We present a series of molecular-mechanics-based protein refinement methods, including two novel ones, applied as part of an induced fit docking procedure. The methods used include minimization; protein and ligand sidechain prediction; a hierarchical ligand placement procedure similar to a-priori protein loop predictions; and a minimized Monte Carlo approach using normal mode analysis as a move step. The results clearly indicate the importance of a proper opening of the active site backbone, which might not be accomplished when the ligand degrees of freedom are prioritized. The most accurate method consisted of the minimized Monte Carlo procedure designed to open the active site followed by a hierarchical optimization of the sidechain packing around a mobile flexible ligand. The methods have been used on a series of 88 protein-ligand complexes including both cross-docking and apo-docking members resulting in complex conformations determined to within 2.0 Å heavy-atom RMSD in 75% of cases where the protein backbone rearrangement upon binding is less than 1.0 Å α-carbon RMSD. We also demonstrate that physics-based all-atom potentials can be more accurate than docking-style potentials when complexes are sufficiently refined. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

An atomic force field for simulating copper clusters and nanoparticles is developed. More than 2000 cluster configurations of varying size and shape are used to constrain the parametrization of the copper force field. Binding energies for these training clusters were computed using density functional theory. Extensive testing shows that the copper force field is fast and reliable for near-equilibrium structures of clusters, ranging from only a few atoms to large nanoparticles that approach bulk structure. Nonequilibrium dissociation and compression structures that are included in the training set are also well described by the force field. Implications for molecular dynamics simulations and extensions to other metallic and covalent systems are discussed. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009 [ABSTRACT FROM AUTHOR]

We illustrate the application of Bennett's acceptance ratio method (BAR) to problems in which standard methods to compute free energy differences (thermodynamic integration, exponential formula) are not practical. Our starting point is the observation that BAR can often compute the free energy difference between two states without the need for intermediate states usually employed (and necessary) in alchemical free energy simulations. This is demonstrated first for the free energy difference between ethane and methanol in aqueous solution. We then show how BAR can be used to compute directly rather unusual free energy differences, such as the free energy difference resulting from changing the treatment of electrostatic interactions, from switching the force field, or from using an implicit solvent model. Calculations of this kind should prove useful for force field development and the validation of implicit solvent methods. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009 [ABSTRACT FROM AUTHOR]

We have calculated the binding free energies of a series of benzamidine-like inhibitors to trypsin with a polarizable force field using both explicit and implicit solvent approaches. Free energy perturbation has been performed for the ligands in bulk water and in protein complex with molecular dynamics simulations. The binding free energies calculated from explicit solvent simulations are well within the accuracy of experimental measurement and the direction of change is predicted correctly in all cases. We analyzed the molecular dipole moments of the ligands in gas, water and protein environments. Neither binding affinity nor ligand solvation free energy in bulk water shows much dependence on the molecular dipole moments of the ligands. Substitution of the aromatic or the charged group in the ligand results in considerable change in the solvation energy in bulk water and protein whereas the binding affinity varies insignificantly due to cancellation. The effect of chemical modification on ligand charge distribution is mostly local. Replacing benzene with diazine has minimal impact on the atomic multipoles at the amidinium group. We have also utilized an implicit solvent based end-state approach to evaluate the binding free energies of these inhibitors. In this approach, the polarizable multipole model combined with Poisson-Boltzmann/surface area (PMPB/SA) provides the electrostatic interaction energy and the polar solvation free energy. Overall the relative binding free energies obtained from the MM-PMPB/SA model are in good agreement with the experimental data. © 2009 Wiley Periodicals, Inc. J Comput Chem 2009 [ABSTRACT FROM AUTHOR]

Tetracyclines (Tcs) are an important family of antibiotics that bind to the ribosome and several proteins. To model Tc interactions with protein and RNA, we have developed a molecular mechanics force field for 12 tetracyclines, consistent with the CHARMM force field. We considered each Tc variant in its zwitterionic tautomer, with and without a bound Mg2+. We used structures from the Cambridge Crystallographic Data Base to identify the conformations likely to be present in solution and in biomolecular complexes. A conformational search by simulated annealing was undertaken, using the MM3 force field, for tetracycline, anhydrotetracycline, doxycycline, and tigecycline. Resulting, low-energy structures were optimized with an ab initio method. We found that Tc and its analogs all adopt an extended conformation in the zwitterionic tautomer and a twisted one in the neutral tautomer, and the zwitterionic-extended state is the most stable in solution. Intermolecular force field parameters were derived from a standard supermolecule approach: we considered the ab initio energies and geometries of a water molecule interacting with each Tc analog at several different positions. The final, rms deviation between the ab initio and force field energies, averaged over all forms, was 0.35 kcal/mol. Intramolecular parameters were adopted from either the standard CHARMM force field, the ab initio structure, or the earlier, plain Tc force field. The model reproduces the ab initio geometry and flexibility of each Tc. As tests, we describe MD and free energy simulations of a solvated complex between three Tcs and the Tet repressor protein. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [ABSTRACT FROM AUTHOR]

We present an all-atom additive empirical force field for the hexopyranose monosaccharide form of glucose and its diastereomers allose, altrose, galactose, gulose, idose, mannose, and talose. The model is developed to be consistent with the CHARMM all-atom biomolecular force fields, and the same parameters are used for all diastereomers, including both the α- and β-anomers of each monosaccharide. The force field is developed in a hierarchical manner and reproduces the gas-phase and condensed-phase properties of small-molecule model compounds corresponding to fragments of pyranose monosaccharides. The resultant parameters are transferred to the full pyranose monosaccharides, and additional parameter development is done to achieve a complete hexopyranose monosaccharide force field. Parametrization target data include vibrational frequencies, crystal geometries, solute–water interaction energies, molecular volumes, heats of vaporization, and conformational energies, including those for over 1800 monosaccharide conformations at the MP2/cc-pVTZ//MP2/6-31G(d) level of theory. Although not targeted during parametrization, free energies of aqueous solvation for the model compounds compare favorably with experimental values. Also well-reproduced are monosaccharide crystal unit cell dimensions and ring pucker, densities of concentrated aqueous glucose systems, and the thermodynamic and dynamic properties of the exocyclic torsion in dilute aqueous systems. The new parameter set expands the CHARMM additive force field to allow for simulation of heterogeneous systems that include hexopyranose monosaccharides in addition to proteins, nucleic acids, and lipids. © 2008 Wiley Periodicals, Inc. J Comput Chem 2008 [ABSTRACT FROM AUTHOR]

The CHARMM force field for DMPC lipids was modified in order to improve agreement with experiment for a number of important properties of hydrated lipid bilayer. The modification consists in introduction of a scaling factor 0.83 for 1–4 electrostatic interactions (between atoms separated by three covalent bonds), which provides correct transgauche ratio in the alkane tails, and recalculation of the headgroup charges on the basis of HF/6-311(d,p) ab-initio computations. Both rigid TIP3P and flexible SPC water models were used with the new lipid model, showing similar results. The new model in a 75 ns simulation has shown a correct value of the area per lipid at zero surface tension, as well as good agreement with the experiment for the electron density, structure factor, and order parameters, including those in the headgroup part of lipids. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [ABSTRACT FROM AUTHOR]

In a previous work we have introduced an intramolecular induction correction model. In this work we have used the model to calculate the total dipol moment of six molecules as a function of two or three dihedral angles that are simultaneously varied in the molecules. It is found that the induction model behaves very well for the systems studied when compared with a regular force field model where fixed charges and dipoles are rotated along with the atoms of the molecules. This suggests that the proposed induction correction model can be used to model systems containing several dihedral angles around which rotations are performed. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [ABSTRACT FROM AUTHOR]

On the basis of quantum chemical calculations Cα-glycyl radical parameters have been developed for the OPLS-AA/L force field. The molecular mechanics hypersurface was fitted to the calculated quantum chemical surface by minimizing their molecular mechanics parameter dependent sum-of-squares deviations. To do this, a computer program in which the molecular mechanics energy derivatives with respect to the parameters were calculated analytically was developed, implementing the general method of Lifson and Warshel (J Chem Phys 1968, 49, 5116) for force field parameter optimization. This program, in principle, can determine the optimal parameter set in one calculation if enough representative value points on the quantum chemical potential energy surface are available and there is no linear dependency between the parameters. Some of the parameters in quantum calculations, including several new torsion types around a bond as well as angle parameters at a new central atom type, are not completely separable. Consequently, some restrictions and/or presumptions were necessary during parameter optimization. The relative OPLS-AA energies reproduced those calculated quantum chemically almost perfectly. © 2008 Wiley Periodicals, Inc. J Comput Chem 2008 [ABSTRACT FROM AUTHOR]

Molecular dynamics (MD) simulations are extensively used in the study of the structures and functions of proteins. Ab initio protein structure prediction is one of the most important subjects in computational biology, and many trials have been performed using MD simulation so far. Since the results of MD simulations largely depend on the force field, reliable force field parameters are indispensable for the success of MD simulation. In this work, we have modified atom charges in a standard force field on the basis of water-phase quantum chemical calculations. The modified force field turned out appropriate for ab initio protein structure prediction by the MD simulation with the generalized Born method. Detailed analysis was performed in terms of the conformational stability of amino acid residues, the stability of secondary structure of proteins, and the accuracy for prediction of protein tertiary structure, comparing the modified force field with a standard one. The energy balance between α-helix and β-sheet structures was significantly improved by the modification of charge parameters. © 2008 Wiley Periodicals, Inc. J Comput Chem 2008 [ABSTRACT FROM AUTHOR]

A method to compute distributed dipole–quadrupole polarizabilities is suggested. The method is based on numerical differentiation of distributed quadrupole moments, using finite field perturbation calculations. It is tested using two different multicenter multipole expansions, and compared with results using polarizabilities obtained via the uncoupled Hartree–Fock approximation. The accuracy of these dipole–quadrupole polarizabilities are tested for different molecules and basis sets, by comparing the induced electrostatic potential of the Hartree–Fock density with the induced electrostatic potential of the polarization models. This is done by perturbing the molecules with an external homogeneous field and with an external dipole. It is found that inclusion of the dipole–quadrupole polarizability significantly improves the accuracy of the response of the molecule to these external perturbations. This suggests that inclusion of higher-order induced moments can be of importance when improving the description of intermolecular interactions using force fields. © 2008 Wiley Periodicals, Inc. J Comput Chem 2008 [ABSTRACT FROM AUTHOR]

A model for intramolecular polarization is presented. It is used to describe the changes in the molecular charge distribution occurring as a response to changes of dihedral angles in the molecule. The model is based on a multicenter multipole distribution of the molecular charge distribution. The electric field from this charge distribution induce dipole moments in the same molecule. The model contains atom type parameters to describe the damping of the electric field. A total of four atom types are used. The parameters are fitted to a calibration set with various functional groups, and tested against a validation set. The error obtained for the calibration set is reduced by 92% and by 88% for the validation set, if compared to an accurate state-of-the-art force field. It is shown that rotating the non-polarizable multicenter multipole distribution for the equilibrium geometry gives too large dipole moments for dihedral angles deviating from the equilibrium geometry. This will lead to too large long-range attractions in simulations. This problem is overcome by using the dipole polarizability correction suggested here, which gives dipole moments very close to the Hartree-Fock dipole moments obtained from reference calculations. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008 [ABSTRACT FROM AUTHOR]