Evaluation Of Force Fields Research Articles

Physics-Based Scoring of Protein–Ligand Interactions: Explicit Polarizability, Quantum Mechanics and Free Energies

The ability to accurately predict the interaction of a ligand with its receptor is a key limitation in computer-aided drug design approaches such as virtual screening and de novo design. In this article, we examine current strategies for a physics-based approach to scoring of protein-ligand affinity, as well as outlining recent developments in force fields and quantum chemical techniques. We also consider advances in the development and application of simulation-based free energy methods to study protein-ligand interactions. Fuelled by recent advances in computational algorithms and hardware, there is the opportunity for increased integration of physics-based scoring approaches at earlier stages in computationally guided drug discovery. Specifically, we envisage increased use of implicit solvent models and simulation-based scoring methods as tools for computing the affinities of large virtual ligand libraries. Approaches based on end point simulations and reference potentials allow the application of more advanced potential energy functions to prediction of protein-ligand binding affinities. Comprehensive evaluation of polarizable force fields and quantum mechanical (QM)/molecular mechanical and QM methods in scoring of protein-ligand interactions is required, particularly in their ability to address challenging targets such as metalloproteins and other proteins that make highly polar interactions. Finally, we anticipate increasingly quantitative free energy perturbation and thermodynamic integration methods that are practical for optimization of hits obtained from screened ligand libraries.

Evaluation and Improvement of the Amber ff99SB Force Field with an Advanced Water Model

A recurring concern when studying biomolecules with molecular dynamics (MD) simulations is the accuracy of the underlying force field and solvent model. These considerations are especially relevant for simulations of intrinsically disordered peptides and proteins, for which energy differences between conformations are small and interactions with water are enhanced. In this work, we investigate the accuracy of the AMBER ff99SB force field, combined with either the TIP3P or the TIP4P-Ew water model, using both conventional MD and replica exchange MD (REMD) simulations to generate conformational ensembles for (disordered) trialanine, triglycine, and trivaline peptides.We find that the TIP4P-Ew water model yields significantly better agreement with experimentally measured scalar couplings - and therefore more accurate conformational ensembles - for both trialanine and triglycine. For trivaline, however, we find that the TIP3P and TIP4P-Ew ensembles are equivalent in accuracy. To address this discrepancy and further improve the force field, we derive new van der Waals parameters for alkanes in TIP4P-Ew water and a straightforward perturbation to the f backbone dihedral potential that shifts the β-PPII equilibrium. Of the two, we find that the revised f backbone dihedral potential is more effective and yields significantly improved conformational ensembles for both the trialanine and trivaline peptides in TIP4P-Ew water.

Simulations of a Protein Crystal with a High Resolution X-ray Structure: Evaluation of Force Fields and Water Models

We use classical molecular dynamics and 16 combinations of force fields and water models to simulate a protein crystal observed by room-temperature X-ray diffraction. The high resolution of the diffraction data (0.96 Å) and the simplicity of the crystallization solution (nearly pure water) make it possible to attribute any inconsistencies between the crystal structure and our simulations to artifacts of the models rather than inadequate representation of the crystal environment or uncertainty in the experiment. All simulations were extended for 100 ns of production dynamics, permitting some long-time scale artifacts of each model to emerge. The most noticeable effect of these artifacts is a model-dependent drift in the unit cell dimensions, which can become as large as 5% in certain force fields; the underlying cause is the replacement of native crystallographic contacts with non-native ones, which can occur with heterogeneity (loss of crystallographic symmetry) in simulations with some force fields. We find that the AMBER FF99SB force field maintains a lattice structure nearest that seen in the X-ray data, and produces the most realistic atomic fluctuations (by comparison to crystallographic B-factors) of all the models tested. We find that the choice of water model has a minor effect in comparison to the choice of protein model. We also identify a number of artifacts that occur throughout all of the simulations: excessive formation of hydrogen bonds or salt bridges between polar groups and loss of hydrophobic interactions. This study is intended as a foundation for future work that will identify individual parameters in each molecular model that can be modified to improve their representations of protein structure and thermodynamics.

Assessment of the Transferability of a Protein Force Field for the Simulation of Peptide-Surface Interactions

In order to evaluate the transferability of existing empirical force fields for all-atom molecular simulations of protein adsorption behavior, we have developed and applied a method to calculate the adsorption free energy (DeltaG(ads)) of model peptides on functionalized surfaces for comparison with available experimental data. Simulations were conducted using the CHARMM program and force field using a host-guest peptide with the sequence TGTG-X-GTGT (where G and T are glycine and threonine amino acid residues, respectively, with X representing valine, threonine, aspartic acid, phenylalanine or lysine) over nine different functionalized alkanethiol self-assembled monolayer (SAM) surfaces with explicitly represented solvent. DeltaG(ads) was calculated using biased-energy replica exchange molecular dynamics to adequately sample the conformational states of the system. The simulation results showed that the CHARMM force-field was able to represent DeltaG(ads) within 1 kcal/mol of the experimental values for most systems, while deviations as large as 4 kcal/mol were found for others. In particular, the simulations reveal that CHARMM underestimates the strength of adsorption on the hydrophobic and positively charged amine surfaces. These results clearly show that improvements in force field parameterization are needed in order to accurately represent interactions between amino acid residues and functional groups of a surface and they provide a means for force field evaluation and modification for the eventual development and validation of an interfacial force field for the accurate simulation of protein adsorption behavior.

Force Field Evaluation for Biomolecular Simulation: Free Enthalpies of Solvation of Polar and Apolar Compounds in Various Solvents

Recently, the GROMOS biomolecular force field parameter set 53A6--which has been parametrized to reproduce experimentally determined free enthalpies of hydration and solvation in cyclohexane of amino acid side-chain analogs--was presented. To investigate the transferability of the new parameter set, we calculated free enthalpies of solvation of a range of polar and apolar compounds in different solvents (methanol, dimethyl sulfoxide (DMSO), acetonitrile, and acetone) from molecular dynamics simulations using the GROMOS 53A6 force field. For methanol and DMSO, parameters were used that are available in the 53A6 parameter set. For acetonitrile, a recently developed model was taken and for acetone, two models available in literature were used. We found that trends in and values for the solvation free enthalpies are in satisfactory agreement with experiment, except for the solvation in acetone for which deviations from experiment can be explained in terms of the properties of the models used.

Evaluation of Force Fields for Molecular Simulation of Polyhedral Oligomeric Silsesquioxanes

Polyhedral oligomeric silsesquioxanes (POSS) are nanometer-size molecules suitable for the production of organic-inorganic nanocomposite materials. These organic-inorganic nano-building blocks show promise for enabling the production of polymeric materials of exceptional mechanical properties as well as novel composite materials. While the experimental studies of these materials have rapidly evolved in the past decade, their theoretical investigation is still in its infancy. Toward the validation of force fields for the molecular simulation of POSS-containing systems, we present the charge-transfer reactive (CTR) force field for the molecular simulation of polyhedral oligomeric silsesquioxane (POSS) molecules and compare the ability of this, and several force fields taken from the literature, to predict the thermophysical properties of POSS-containing systems. The literature force fields compared include the universal force field (UFF) and the COMPASS and Hybrid-COMPASS force fields. Predictions from molecular dynamics simulations of the structural parameters (unit cell vectors), melting temperature, and FT-IR spectra of crystals of POSS monomers are presented. The POSS monomers investigated are octahydride, octamethyl, and octapropyl POSS. Predicted quantities are compared to experimental results where available and provide molecular-level physical insight into several aspects of the behavior of POSS molecules. While all the force fields tested perform reasonably well, our results indicate that the Hybrid-COMPASS and CTR force fields predict structural properties that are in good agreement with experimental data.

A Method for Induced-Fit Docking, Scoring, and Ranking of Flexible Ligands. Application to Peptidic and Pseudopeptidic β-secretase (BACE 1) Inhibitors

Inhibition of beta-secretase (BACE 1) has recently been investigated as a promising therapeutic approach in the treatment of Alzheimer's disease, and a growing number of BACE 1 inhibitors and crystal structures of BACE 1/inhibitors complexes have been reported. We report herein a predictive computational method and its application to potential BACE 1 inhibitors. Using a training set of 50 known highly flexible inhibitors, we developed a docking method that accounts for the flexibility of both the protein and the inhibitors. Protein flexibility is accounted for using a specifically designed genetic algorithm. We next developed a scoring function consisting of force field evaluation of the inhibitor/protein interactions and two additional terms for hydrogen bonding and entropy change upon binding. Discarding three outliers from the training set, our protocol was found to perform well with an rmsd of 1.19 kcal/mol. Evaluation of the predictive power was next carried out by virtual screening of 80 synthetic compounds. The significant enrichment at the top of the ranking list in active compounds demonstrated the ability of the docking and scoring protocol to rank the compounds relative to their activities.

Evaluation of carbohydrate molecular mechanical force fields by quantum mechanical calculations

A quantitative evaluation of 20 second-generation carbohydrate force fields was carried out using ab initio and density functional methods. Geometry-optimized structures (B3LYP/6-31G(d)) and relative energies using augmented correlation consistent basis sets were calculated in gas phase for monosaccharide carbohydrate benchmark systems. Selected results are: (i) The interaction energy of the α- d-glucopyranose·H 2O heterodimer is estimated to be 4.9 kcal/mol, using a composite method including terms at highly correlated (CCSD(T)) level. Most molecular mechanics force fields are in error in this respect; (ii) The 3E envelope ( south) pseudorotational conformer of methyl 5-deoxy-β- d-xylofuranoside is 0.66 kcal/mol more stable than the 3E envelope ( north) conformer and the α-anomer of methyl d-glucopyranoside is 0.82 kcal/mol more stable than the β-anomer; (iii) The relative energies of the ( gg, gt and tg) rotamers of methyl α- d-glucopyranoside and methyl α- d-galactopyranoside are (0.13, 0.00, 0.15) and (0.64, 0.00, 0.77) kcal/mol, respectively. The results of the quantum mechanical calculations are compared with the results of calculations using the 20 second-generation carbohydrate force fields. No single force field is consistently better than the others for all the test cases. A statistical assessment of the performance of the force fields indicates that CHEAT(95), CFF, certain versions of Amber and of MM3 have the best overall performance, for these gas phase monosaccharide systems.

A new look at the atomic level virial stress: on continuum-molecular system equivalence

The virial stress is the most commonly used definition of stress in discrete particle systems. This quantity includes two parts. The first part depends on the mass and velocity (or, in some versions, the fluctuation part of the velocity) of atomic particles, reflecting an assertion that mass transfer causes mechanical stress to be applied on stationary spatial surfaces external to an atomic‐particle system. The second part depends on interatomic forces and atomic positions, providing a continuum measure for the internal mechanical interactions between particles. Historic derivations of the virial stress include generalization from the virial theorem of Clausius (1870) for gas pressure and solution of the spatial equation of balance of momentum. The virial stress is stress‐like a measure for momentum change in space. This paper shows that, contrary to the generally accepted view, the virial stress is not a measure for mechanical force between material points and cannot be regarded as a measure for mechanical stress in any sense. The lack of physical significance is both at the individual atom level in a time‐resolved sense and at the system level in a statistical sense. It is demonstrated that the interatomic force term alone is a valid stress measure and can be identified with the Cauchy stress. The proof in this paper consists of two parts. First, for the simple conditions of rigid translation, uniform tension and tension with thermal oscillations, the virial stress yields clearly erroneous interpretations of stress. Second, the conceptual flaw in the generalization from the virial theorem for gas pressure to stress and the confusion over spatial and material equations of balance of momentum in theoretical derivations of the virial stress that led to its erroneous acceptance as the Cauchy stress are pointed out. Interpretation of the virial stress as a measure for mechanical force violates balance of momentum and is inconsistent with the basic definition of stress. The versions of the virial‐stress formula that involve total particle velocity and the thermal fluctuation part of the velocity are demonstrated to be measures of spatial momentum flow relative to, respectively, a fixed reference frame and a moving frame with a velocity equal to the part of particle velocity not included in the virial formula. To further illustrate the irrelevance of mass transfer to the evaluation of stress, an equivalent continuum (EC) for dynamically deforming atomistic particle systems is defined. The equivalence of the continuum to discrete atomic systems includes (i) preservation of linear and angular momenta, (ii) conservation of internal, external and inertial work rates, and (iii) conservation of mass. This equivalence allows fields of work‐ and momentum‐preserving Cauchy stress, surface traction, body force and deformation to be determined. The resulting stress field depends only on interatomic forces, providing an independent proof that as a measure for internal material interaction stress is independent of kinetic energy or mass transfer.

Fast evaluation of potential and force field in particle systems using a fair-split tree spatial structure

We consider the following force field computation problem: given a duster of n particles in 3-dimensional space, compute the force exerted on each particle by the other particles. Depending on different applications, the pairwise interaction could be either gravitational or Lennard Jones. Since there are n(n−1)/2pairs, direct method requires θ(n2) time. In this paper, we report our computational experiences with a new O(nlogn) time algorithm for fast evaluation of potential and force field in large Lennard – Jones clusters. This algorithm is based on a fair-split tree which guarantees O(nlogn)worst-case time complexity without any restriction on particle distributions. For randomly generated particle systems, our implementation outperforms the direct method when the number of panicles is 500 or larger This is the lowest cross over point ever reported in the literature.

Minimum Inter-Particle Distance at Global Minimizers of Lennard-Jones Clusters

In computer simulations of molecular conformation and protein folding, a significant part of computing time is spent in the evaluation of potential energy functions and force fields. Therefore many algorithms for fast evaluation of potential energy functions and force fields are proposed in the literature. However, most of these algorithms assume that the particles are uniformly distributed in order to guarantee good performance. In this paper, we prove that the minimum inter-particle distance at any global minimizer of Lennard-Jones clusters is bounded away from zero by a positive constant which is independent of the number of particles. As a by-product, we also prove that the global minimum of an n particle Lennard-Jones cluster is bounded between two linear functions. Our first result is useful in the design of fast algorithms for potential function and force field evaluation. Our second result can be used to decide how good a local minimizer is.

Stochastic approach to force field evaluations: conformational analysis of raloxifene, a potential new therapeutic agent for post-menopausal osteoporosis

Three widely used force fields are compared with regard to their ability to describe conformer populations. The test molecule is raloxifene, an exciting new potential medicine for treating postmenopausal osteoporosis in women. The TRIPOS (Sybyl), MM3, and UFF force fields are used to sample the low energy conformations of the long piperidinium-containing side chain of this selective estrogen receptor modulator. In this test, the conformer populations are particularly affected by nonbonded interactions. MM3 gives reasonable results, as does the UFF force field, although the latter is sensitive to the setup of a conformational search calculation. The TRIPOS (Sybyl) force field overestimates nonbonded attractions, thus biasing the conformer population toward folded structures in which the cationic ring abuts the phenolic ring.

Stochastic approach to force field evaluations: conformational analysis of raloxifene, a potential new therapeutic agent for post-menopausal osteoporosis

Three widely used force fields are compared with regard to their ability to describe conformer populations. The test molecule is raloxifene, an exciting new potential medicine for treating postmenopausal osteoporosis in women. The TRIPOS (Sybyl), MM3, and UFF force fields are used to sample the low energy conformations of the long piperidinium-containing side chain of this selective estrogen receptor modulator. In this test, the conformer populations are particularly affected by nonbonded interactions. MM3 gives reasonable results, as does the UFF force field, although the latter is sensitive to the setup of a conformational search calculation. The TRIPOS (Sybyl) force field overestimates nonbonded attractions, thus biasing the conformer population toward folded structures in which the cationic ring abuts the phenolic ring.

Molecular reinforcement: A force field evaluation

AbstractComputer simulations on the basis of a force field approach are used to test the concept of molecular reinforcement and to get an insight into the parameters controlling the reinforcement effect. The finding is that molecular reinforcement may be as effective as fiber reinforcement. The molecular interactions between the matrix and the rigid molecules replace the adhesion between fiber and matrix and the axial ratio of the molecules plays the same role as the axial ratio of the fiber in the case of fiber reinforcement.

Critical Evaluation of Benzene Analytical Nonbonded Force Fields. Reparametrization of the MM3 Potential

Critical Evaluation of Benzene Analytical Nonbonded Force Fields. Reparametrization of the MM3 Potential

Evaluation of harmonic force fields from limited spectroscopic information and calculated Hessian matrices: butadiene

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEvaluation of harmonic force fields from limited spectroscopic information and calculated Hessian matrices: butadieneWeilin Tang and Thomas BallyCite this: J. Phys. Chem. 1993, 97, 17, 4365–4372Publication Date (Print):April 1, 1993Publication History Published online1 May 2002Published inissue 1 April 1993https://doi.org/10.1021/j100119a019RIGHTS & PERMISSIONSArticle Views54Altmetric-Citations17LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (923 KB) Get e-Alerts

Computation of electric fields from electric charges: Coulomb's law or poisson's equation

AbstractCoulomb's Law and Poisson's equation are revisited and compared as algorithms for computer evaluation of electric force fields. In the course of this examination we point to the danger of applying physical laws measured in three‐dimensional space to spaces of other dimensionalities. The algorithms based on Coulomb's Law and on Poisson's equation are cast in C‐language and are illustrated with a two‐dimensional example.

A force field evaluation tool for telephone service in ambulatory health care.

The tool presented here is useful in analyzing the constraints and capabilities of a health care telephone service. It also provides a systematic method for assessing systems problems. As part of our analysis, we recommended that the manager implement the following steps. First, the manager determines whether the driving force on the unit is continuity of care by an individual provider or consistency of response. This focus directly affects how the unit's telephone service can be best organized (i.e., decentralized or centralized) and clarifies the factors most needed for success. For example, to function effectively and efficiently, a centralized phone service needs strong provider-endorsed protocols. Second, the manager should carefully examine neutral constraint factors to determine methods to transform these constraints into capabilities, such as planning for extra staff or office hours (or both) during influenza season. Planning for extra hours or staff depends largely on whether budget and resource planning is done in advance and whether value is placed on customer access and satisfaction during peak demand periods. The manager must next determine whether the service delivery format (centralized or decentralized) is consistent with the force field analysis findings. If the findings are not consistent, can the analysis present a compelling argument for using the opposite approach? Finally, the manager must create a plan of action for minimizing the constraints revealed and maximizing existing capabilities to achieve the overall goal of excellent phone service. The process of analysis and creating a plan of action is an excellent opportunity to involve staff, providers, and administrators in efforts to achieve better health care telephone service for all customers.

Evaluation of vibrational force fields derived by using semiempirical and ab initio methods

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEvaluation of vibrational force fields derived by using semiempirical and ab initio methodsD. M. Seeger, Carol Korzeniewski, and W. KowalchykCite this: J. Phys. Chem. 1991, 95, 18, 6871–6879Publication Date (Print):September 1, 1991Publication History Published online1 May 2002Published inissue 1 September 1991https://doi.org/10.1021/j100171a026RIGHTS & PERMISSIONSArticle Views139Altmetric-Citations79LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (867 KB) Get e-Alerts

A transferable general valence force field for oxalyl halides: fourier transform infrared spectral analysis of oxalyl chloride isolated in cryogenic rare gas matrices

The vibrational potential functions of oxalyl halides (COX) 2 (X = Cl, Br, or F) and C 2O 2XY (X = Cl, Y = F) have been derived from literature values of the experimental frequencies. Internal coordinates used in the force field evaluations have demonstrated small changes in the force constant values related to the common C 2O 2 framework. In xenon and argon matrices, the oxalyl chloride IR spectra show multiplets, associated with natural abundance isotopic shifts and site effects, in agreement with calculated isotopic values. Numerous combination tones have been observed and identified; several are evidently perturbed by strong Fermi resonance.