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Electron paramagnetic resonance (EPR) has become a powerful probe of conformational heterogeneity and dynamics of biomolecules. In this Review, we discuss different computational modeling techniques that enrich the interpretation of EPR measurements of dynamics or distance restraints. A variety of spin labels are surveyed to provide a background for the discussion of modeling tools. Molecular dynamics (MD) simulations of models containing spin labels provide dynamical properties of biomolecules and their labels. These simulations can be used to predict EPR spectra, sample stable conformations and sample rotameric preferences of label sidechains. For molecular motions longer than milliseconds, enhanced sampling strategies and de novo prediction software incorporating or validated by EPR measurements are able to efficiently refine or predict protein conformations, respectively. To sample large‐amplitude conformational transition, a coarse‐grained or an atomistic weighted ensemble (WE) strategy can be guided with EPR insights. Looking forward, we anticipate an integrative strategy for efficient sampling of alternate conformations by de novo predictions, followed by validations by systematic EPR measurements and MD simulations. Continuous pathways between alternate states can be further sampled by WE‐MD including all intermediate states. [ABSTRACT FROM AUTHOR]

Machine learning was employed on the experimental crystal structures of the Cambridge Structural Database (CSD) to derive an intermolecular force field for all available types of atoms (general force field). The obtained pairwise interatomic potentials of the general force field allow for the fast and accurate calculation of intermolecular Gibbs energy. The approach is based on three postulates regarding Gibbs energy: the lattice energy must be below zero, the crystal structure must be a local minimum, and, if available, the experimental and the calculated lattice energy must coincide. The parametrized general force field was then validated regarding these three conditions. First, the experimental lattice energy was compared with the calculated energies. The observed errors were found to be in the order of experimental errors. Second, Gibbs lattice energy was calculated for all structures available in the CSD. Their energy values were found to be below zero in 99.86% of the cases. Finally, 500 random structures were minimized, and the change in density and energy was examined. The mean error in the case of density was below 4.06%, and for energy it was below 5.7%. The obtained general force field calculated Gibbs lattice energies of 259 041 known crystal structures within a few hours. Since Gibbs energy defines the reaction energy, the calculated energy can be used to predict chemical–physical properties of crystals, for instance, the formation of co‐crystals, polymorph stability and solubility. [ABSTRACT FROM AUTHOR]

This paper considers the narrow escape problem of a Brownian particle within a three‐dimensional Riemannian manifold under the influence of the force field. We compute an asymptotic expansion of mean sojourn time for Brownian particles. As a auxiliary result, we obtain the singular structure for the restricted Neumann Green's function which may be of independent interest. [ABSTRACT FROM AUTHOR]

In molecular modelling of novel solvents such as ionic liquids, it is common to scale atomic charges to improve the experiment‐simulation agreement for some selected properties. As these liquids are designed to solvate solutes, whether the solvation thermodynamics could be correctly described is of utmost importance. Therefore, we present a comprehensive large‐scale calculation of solvation free energies via nonequilibrium fast‐switching simulations for a spectrum of molecules in ionic liquids, the atomic charges of which are scaled to maximize the prediction‐experiment correlation. Further, the density‐derived choice is compared with the solvation‐thermodynamics‐derived one. When the scaling factor is decreased, the density exhibits a monotonically decreasing behavior due to weaker inter‐molecular interactions produced by scaled atomic charges. However, solvation free energies do not show consistent monotonic behaviors, which are caused by competing electrostatic and vdW responses to the scaling‐parameter variation. More intriguingly, the solvation‐free‐energy‐derived scaling factor is generally slightly higher than the density‐derived one. We further calculate partition coefficients ortransfer free energies of solutes from water to ionic liquids to provide another thermodynamic perspective of charge scaling. Another central result is the detailed evaluation of the widely used force fields for bonded and vdW terms, i.e., the GAFF derivatives. [ABSTRACT FROM AUTHOR]

Molecular dynamics (MD) simulation has been widely used in the field of biomedicine to study the conformational transition of proteins caused by mutation or ligand binding/unbinding. It provides some perspectives those are difficult to find in traditional biochemical or pathological experiments, for example, detailed effects of mutations on protein structure and protein–protein/ligand interaction at the atomic level. In this review, a broad overview on conformation changes and drug discovery by MD simulation is given. We first discuss the preparation of protein structure for MD simulation, which is a key step that determines the accuracy of the simulation. Then, we summarize the applications of commonly used force fields and MD simulations in scientific research. Finally, enhanced sampling methods and common applications of these methods are introduced. In brief, MD simulation is a powerful tool and it can be used to guide experimental study. The combination of MD simulation and experimental techniques is an a priori means to solve the biomedical problems and give a deep understanding on the relationship between protein structure and function. [ABSTRACT FROM AUTHOR]

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]

Understanding the ways of interaction of a drug with a biological target is crucial in the pharmacology field. One methodology that allows the simulation of new drugs under in vitro conditions is the classical molecular dynamics (MD) method. However, MD simulations in systems containing metallodrugs are challenging due to the lack of specific parameters found in the literature. In this work, we propose and model a new possible anticancer platinum(II) complex: cis‐dichloro(2‐aminomethylpyridine)platinum(II) bonded to 2‐(4′‐amino‐2′‐hydroxyphenyl)benzothiazole (AHBT). The developed model consists of a new set of AMBER force field parameters based on density functional theory (DFT) calculations. The extensive validation of the parameter set shows that it adequately describes the structural properties of the complex. Overall, we expect this work to contribute significantly to future MD simulations of Pt(II) complexes in biological targets that are still not well explored, mainly due to the few parameters found in the literature. [ABSTRACT FROM AUTHOR]

The possible effect of plastic nanoparticles of waste origin on biological systems is still unclear and could pose a severe threat. Model studies at the molecular level are urgently needed in order to help reveal the interplay between these particles and biological systems, and thereby to indicate the direction of further research. In the present study, simulated annealing molecular dynamics is adjusted and applied to generate an array of conformations for a sample peptide oligoalanine possibly binding to polyethylene and nylon 6,6 nanoplastics. The resulting structures, with a diameter of up to 5 nm, were investigated with the aid of static quantum chemical calculations. The obtained data unequivocally show that both plastic nanoparticles influence the relative stability of α‐helix, β‐hairpin, and other conformations strongly. Polyethylene nanoparticle increases the stability of the helical foldamer. Nylon 6,6 nanoplastic offers strong plastic‐peptide interactions on its surface, making the unfolding of the peptide thermodynamically highly favorable. These results further underscore that nanoplastics can do significant molecular‐level damage to living organisms via facilitating the misfolding and denaturation of proteins. Furthermore, it is apparent that plastics can have very different effects on living matter depending upon their composition, and hence experiments with any single kind of plastics (eg, polystyrene) should not be considered generally valid for all nanoplastics. [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]

Available estimates indicate that 30–40 % of all proteins need at least one metal ion to perform their biological function. Therefore, they are called metalloproteins. The correct biosynthesis of metalloproteins requires living organisms to be able to cope with issues such as the limited bioavailability or the potential cytotoxicity of several essential metals. Thus, organisms have developed complex machineries that guarantee the proper intracellular concentration and distribution among compartments of each metal, i.e. metal homeostasis. To understand how the different proteins responsible for metal homeostasis carry out their function, it is necessary to investigate their three‐dimensional (3D) structure and mobility at the atomic level. Nuclear magnetic resonance spectroscopy is one of the main experimental techniques providing this information. Computer simulations of molecular dynamics (MD) complement experimental information by showing how the 3D structure fluctuates over time and as a function of environmental conditions, with the possibility of exploring a wider range of timescales and conditions than usually amenable to experiment. Here we review numerous applications of MD for the investigation of the structure and dynamics of metalloproteins, and we also mention some technical aspects related to the parametrization of metals in commonly used force fields. Molecular dynamics simulations complement experimental information providing an atomistic view on biological functions. Here we discuss some applications to the study of metalloproteins, from the determination of their 3D structures, to their role in metal storage, transport and metal‐dependent transcriptional regulation. Some technical aspects related to the parametrization of metal ions are also mentioned. [ABSTRACT FROM AUTHOR]

We present a new force field for zinc ion to be used in classical Molecular Dynamics. Such model has been developed according to an optimization procedure by fitting experimental quantities taken from the literature. The metal ion electrostatic charge has been scaled by a factor 0.75, according to a recently proposed polarization model which considers the electronic screening effects due to the surrounding environment. Zinc interatomic interactions have been modeled by means of the Waldman‐Hagler combination rule. It is demonstrated that the proposed force field for zinc is transferable from water solution to protein catalytic sites, offering in both the considered cases good performances in the reproduction of experimental quantities usually addressed in soft matter computer simulations. A new force field for zinc ion, based on the standard Lennard‐Jones plus Coulomb potential, is presented. The ion point charge has been scaled to consider the electronic screening effects due to the environment. Structural and thermodynamic properties in water solution and protein metal centers have been calculated by means of molecular simulations, showing a fair agreement with experimental data. [ABSTRACT FROM AUTHOR]

The key to nanoscale control of physical, chemical, and biological processes lies in well‐founded models of noncovalent binding. Atomistic simulations probe the free‐energy surface underlying molecular assembly processes in solution. Two examples of noncovalent binding studied by molecular dynamics simulations are discussed, the dimerization of a water‐soluble perylene bisimide derivative in aqueous solution with a focus on the influence of solvent composition on the aggregation strength and the binding of 1‐butanol to α‐cyclodextrin at infinite dilution with the focus on the determination of method‐independent binding free energies. The association of molecular building blocks in a given solvent depends in a complex manner on the solvent composition. Molecular dynamics simulations provide a molecular‐level understanding of the various driving forces. In this work, two examples of noncovalent binding are studied and some aspects of force field validation are illustrated. [ABSTRACT FROM AUTHOR]

Intrinsically disordered proteins (IDPs) are closely related to various human diseases. Because IDPs lack certain tertiary structure, it is difficult to use X‐ray and NMR methods to measure their structures. Therefore, molecular dynamics simulation is a useful tool to study the conformer distribution of IDPs. However, most generic protein force fields were found to be insufficient in simulations of IDPs. Here, we report our development for the CHARMM community. Our residue‐specific IDP force field (CHARMM36IDPSFF) was developed based on the base generic force field with CMAP corrections for all 20 naturally occurring amino acids. Multiple tests show that the simulated chemical shifts with the newly developed force field are in quantitative agreement with NMR experiment and are more accurate than the base generic force field. Comparison of J‐couplings with previous work shows that CHARMM36IDPSFF and its corresponding base generic force field have their own advantages. In addition, CHARMM36IDPSFF simulations also agree with experiment for SAXS profiles and radii of gyration of IDPs. Detailed analysis shows that CHARMM36IDPSFF can sample more diverse and disordered conformers. These findings confirm that the newly developed force field can improve the balance of accuracy and efficiency for the conformer sampling of IDPs. [ABSTRACT FROM AUTHOR]

Abstract: Structural characterization of liquid pyrrole has been obtained by performing classical molecular dynamics simulations with a new parameterization of electrostatic interactions. Despite the relatively simple molecular structure of pyrrole, a correct and accurate representation of its intermolecular interactions in bulk phase is a challenging task, since these are affected at short range by the quadrupole–quadrupole term. This new parameterization permits not only to correctly describe the liquid structure but also to obtain macroscopic properties in excellent agreement with experiments. [ABSTRACT FROM AUTHOR]

Abstract: Recently, stereoinversions and isomerizations of amino acid residues in the proteins of living beings have been observed. Because isomerized amino acids cause structural changes and denaturation of proteins, isomerizations of amino acid residues are suspected to cause age‐related diseases. In this study, AMBER molecular force field parameters were tested by using computationally generated nonapeptides and tripeptides including stereoinverted and/or isomerized amino acid residues. Energy calculations by using density functional theory were also performed for comparison. Although the force field parameters were developed by parameter fitting for l‐α‐amino acids, the accuracy of the computational results for d‐amino acids and β‐amino acids was comparable to those for l‐α‐amino acids. The conformational energies for tripeptides calculated by using density functional theory were reproduced more accurately than those for nonapeptides calculated by using the molecular mechanical force field. The evaluations were performed for the ff99SB, ff03, ff12SB, and the latest ff14SB force field parameters. [ABSTRACT FROM AUTHOR]

Free-energy calculations based on molecular simulations provide access to a wide range of thermodynamic properties such as the solubility and partitioning of a molecule in and between various phases. It is demonstrated how molecular dynamics free-energy simulations may be used to obtain the solubilities of primary alcohols and n-alkanes in water and binding affinities of primary alcohols to α-cyclodextrin. The equivalence of two distinct routes to calculate binding free energies is shown leading to the conclusion that host-guest binding affinities may be used to probe the underlying molecular force field. [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]

Intrinsically disordered proteins are proteins which lack of specific tertiary structure and unable to fold spontaneously without the partner binding. These intrinsically disordered proteins are found to associate with various diseases, such as diabetes, cancer, and neurodegenerative diseases. However, current widely used force fields, such as ff99SB, ff14SB, OPLS/AA, and Charmm27, are insufficient in sampling the conformational characters of intrinsically disordered proteins. In this study, the CMAP method was used to correct the φ/ ψ distributions of disorder-promoting amino acids. The simulation results show that the force filed parameters ( ff14IDPs) can improve the φ/ ψ distributions of the disorder-promoting amino acids, with RMSD less than 0.10% relative to the benchmark data of intrinsically disordered proteins. Further test suggests that the calculated secondary chemical shifts under ff14IDPs are in quantitative agreement with the data of NMR experiment for five tested systems. In addition, the simulation results show that ff14IDPs can still be used to model structural proteins, such as tested lysozyme and ubiquitin, with better performance in coil regions than the original general Amber force field ff14SB. These findings confirm that the newly developed Amber ff14IDPs is a robust model for improving the conformation sampling of intrinsically disordered proteins. [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]

A non-polarizable force field based on atomic multipoles fit to reproduce experimental crystal properties and ab initio gas-phase dimers is described. The Ewald method is used to calculate both long-range electrostatic and 1/ r6 dispersion energies of crystals. The dispersion energy of a crystal calculated by a cutoff method is shown to converge slowly to the exact Ewald result. A method for constraining space-group symmetry during unit-cell optimization is derived. Results for locally optimizing 4427 unit cells including volume, cell parameters, unit-cell r.m.s.d. and CPU timings are given for both flexible and rigid molecule optimization. An algorithm for randomly generating rigid molecule crystals is described. Using the correct experimentally determined space group, the average and maximum number of random crystals needed to find the correct experimental structure is given for 2440 rigid single component crystals. The force field energy rank of the correct experimental structure is presented for the same set of 2440 rigid single component crystals assuming the correct space group. A complete crystal prediction is performed for two rigid molecules by searching over the 32 most probable space groups. [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]

The prediction of mutation-induced free-energy changes in protein thermostability or protein-protein binding is of particular interest in the fields of protein design, biotechnology, and bioengineering. Herein, we achieve remarkable accuracy in a scan of 762 mutations estimating changes in protein thermostability based on the first principles of statistical mechanics. The remaining error in the free-energy estimates appears to be due to three sources in approximately equal parts, namely sampling, force-field inaccuracies, and experimental uncertainty. We propose a consensus force-field approach, which, together with an increased sampling time, leads to a free-energy prediction accuracy that matches those reached in experiments. This versatile approach enables accurate free-energy estimates for diverse proteins, including the prediction of changes in the melting temperature of the membrane protein neurotensin receptor 1. [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]

Metal-organic frameworks (MOFs) are attracting much attention as promising materials for gas separation. Given the large number of design possibilities in the MOF materials space, it is desirable to efficiently characterize their performance prior to their experimental synthesis. This Perspective focuses on some of the works that have been put forth in developing new methods that accurately describe the thermodynamics of gas uptake in MOFs by making use of a few selected ab initio calculations. We provide a future outlook toward a full ab initio description of these properties using efficient sampling strategies in conjunction with faster and more accurate quantum methods. © 2015 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]

Force field accuracy is still one of the "stalemates" in biomolecular modeling. Model systems with high quality experimental data are valuable instruments for the validation and improvement of effective potentials. With respect to protein-ligand binding, organic host-guest complexes have long served as models for both experimental and computational studies because of the abundance of binding affinity data available for such systems. Binding affinity data collected for cyclodextrin (CD) inclusion complexes, a popular model for molecular recognition, is potentially a more reliable resource for tuning energy parameters than hydration free energy measurements. Convergence of binding free energy calculations on CD host-guest systems can also be obtained rapidly, thus offering the opportunity to assess the robustness of these parameters. In this work, we demonstrate how implicit solvent parameters can be developed using binding affinity experimental data and the binding energy distribution analysis method (BEDAM) and validated using the Grid Inhomogeneous Solvation Theory analysis. These new solvation parameters were used to study protein-ligand binding in two drug targets against the HIV-1 virus and improved the agreement between the calculated and the experimental binding affinities. This work illustrates how benchmark sets of high quality experimental binding affinity data and physics-based binding free energy models can be used to evaluate and optimize force fields for protein-ligand systems. [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]

An important high-temperature polyimide, namely HFPE-30, has been coarse grained to three different levels of detail. It has been shown that while it is possible to successfully calibrate bonded and non-bonded forcefields and attain realistic densities with all levels of coarse graining, reproducing chain structures and dynamic properties requires an adequate level of atomistic detail to be retained. A model that coarse grains the HFPE-30 molecule into eight beads, approximates both chain structure and dynamic properties well. Alternately, the unrealistically fast dynamics in coarse-grained models can be slowed down by increasing the thermal coupling constant by a scaling factor that is estimated by comparing mean square displacements in detailed atomistic and coarse-grained simulations. In general, stress-strain responses of coarse-grained systems do not match those of the detailed atomic systems except when the coarse graining involves eight beads. In cases where lesser number of beads are used, slowing the dynamics down by the estimated scaling factor takes the stress-strain response of the coarse-grained system close to that of the detailed atomistic one. [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]

Molecular dynamics (MD) simulation can give a detailed picture of conformational equilibria of biomolecules, but it is only reliable if the force field used in the simulation is accurate, and the sampling of the conformational space accessible to the biomolecule shows many (un)folding transitions to allow for precise averages of observable quantities. Here, the use of coarse-grained (CG) solvent MeOH and H2O models to speed up the sampling of the conformational equilibria of an octa- β-peptide is investigated. This peptide is thought to predominantly adopt a 314-helical fold when solvated in MeOH, and a hairpin fold when solvated in H2O on the basis of the NMR data. Various factors such as the chirality of a residue, a force-field modification for the solute, coarse-graining of the solvent model, and an extension of the nonbonded interaction cut-off radius are shown to influence the simulated conformational equilibria and the agreement with the experimental NMR data for the octa- β-peptide. [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]

Density functional calculations are used to investigate the interatomic forces that arise if Ti atoms are substituted by Ni or Cu defect atoms. For the experimentally found monoclinic B19' ground state structure, these forces are calculated for the unrelaxed atomic positions by the Korringa-Kohn-Rostoker Green-function method. The force field in the vicinity of the defects is markedly different in 32- and 256-atom supercells while it is nearly the same in 256- and 2048-atom supercells. This difference is explained by symmetry arguments and discussed as a possible explanation for the concentration dependent transition from the high-temperature B2 phase to low temperature B19' or strain glass phases. [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]

A structural and vibrational study on the antiviral deoxyribonucleoside thymidine in gas and aqueous solution phases was performed combining the available infrared and Raman spectra with density functional theory (DFT) calculations. Three stable conformers for the title molecule were theoretically determined in both media by using the hybrid B3LYP method together with the 6-31G* basis set. The solvent effects were studied by means of the self-consistent reaction field method employing the polarized continuum model. Complete assignments of the vibrational spectra of thymidine in both phases were performed combining the DFT calculations with Pulay's scaled quantum mechanics force field methodology. The bond orders, atomic charges, solvation energies, dipole moments, molecular electrostatic potentials, and force constants parameters were calculated for the three conformers of thymidine in gas phase and aqueous solution. Selected descriptors, such as chemical potential ( µ), electronegativity ( χ), global hardness ( η), global softness ( S), and global electrophilicity index ( ω) were used to explain the exact nature of the interactions with electrophiles and/or nucleophiles and to predict the behavior of the three conformers of thymidine in gas and aqueous solution phases. © 2013 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]