ForceFit: A code to fit classical force fields to quantum mechanical potential energy surfaces

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     

Three-site and five-site fixed-charge water models compatible with AMOEBA force field

In a typical biomolecular simulation using Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field, the vast majority molecules in the simulation box consist of water, and these water molecules consume the most CPU power due to the explicit mutual induction effect. To improve the computational efficiency, we here develop two new nonpolarizable water models (with flexible bonds and fixed charges) that are compatible with AMOEBA solute: the 3-site AW3C and 5-site AW5C. To derive the force-field parameters for AW3C and AW5C, we fit to six experimental liquid thermodynamic properties: liquid density, enthalpy of vaporization, dielectric constant, isobaric heat capacity, isothermal compressibility and thermal expansion coefficient, at a broad range of temperatures from 261.15 to 353.15 K under 1.0 atm pressure. We further validate our AW3C and AW5C water models by showing that they can well reproduce the radial distribution function g(r), self-diffusion constant D, and hydration free energy from the AMOEBA03 water model and the experimental observations. Furthermore, we show that our AW3C and AW5C water models can greatly accelerate (>5 times) the bulk water as well as biomolecular simulations when compared to AMOEBA water. Specifically, we demonstrate that the applications of AW3C and AW5C water models to simulate a DNA duplex lead to a threefold acceleration, and in the meanwhile well maintain the structural properties as the fully polarizable AMOEBA water. We expect that our AW3C and AW5C water models hold great promise to be widely applied to simulate complex bio-molecules using the AMOEBA force field.     

The adaptive buffered force QM/MM method in the CP2K and AMBER software packages

The implementation and validation of the adaptive buffered force (AdBF) quantum‐mechanics/molecular‐mechanics (QM/MM) method in two popular packages, CP2K and AMBER are presented. The implementations build on the existing QM/MM functionality in each code, extending it to allow for redefinition of the QM and MM regions during the simulation and reducing QM‐MM interface errors by discarding forces near the boundary according to the buffered force‐mixing approach. New adaptive thermostats, needed by force‐mixing methods, are also implemented. Different variants of the method are benchmarked by simulating the structure of bulk water, water autoprotolysis in the presence of zinc and dimethyl‐phosphate hydrolysis using various semiempirical Hamiltonians and density functional theory as the QM model. It is shown that with suitable parameters, based on force convergence tests, the AdBF QM/MM scheme can provide an accurate approximation of the structure in the dynamical QM region matching the corresponding fully QM simulations, as well as reproducing the correct energetics in all cases. Adaptive unbuffered force‐mixing and adaptive conventional QM/MM methods also provide reasonable results for some systems, but are more likely to suffer from instabilities and inaccuracies. © 2015 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

Application of polarizable ellipsoidal force field model to pnicogen bonds

Noncovalent interactions, such as hydrogen bonds and halogen bonds, are frequently used in drug designing and crystal engineering. Recently, a novel noncovalent pnicogen bonds have been identified as an important driving force in crystal structures with similar bonding mechanisms as hydrogen bond and halogen bond. Although the pnicogen bond is highly anisotropic, the pnicogen bond angles range from 160° to 180° due to the complicated substituent effects. To understand the anisotropic characters of pnicogen bond, a modification of the polarizable ellipsoidal force field (PEff) model previously used to define halogen bonds was proposed in this work. The potential energy surfaces (PESs) of mono‐ and polysubstituted PH₃–NH₃ complexes were calculated at CCSD(T), MP2, and density functional theory levels and were used to examine the modified PEff model. The results indicate that the modified PEff model can precisely characterize pnicogen bond. The root mean squared error of PES obtained with PEff model is less than 0.5 kcal/mol, compared with MP2 results. In addition, the modified PEff model may be applied to other noncovalent bond interactions, which is important to understand the role of intermolecular interactions in the self‐assembly structures. © 2015 Wiley Periodicals, Inc.     

Developing ab initio quality force fields from condensed phase quantum-mechanics/molecular-mechanics calculations through the adaptive force matching method

A new method called adaptive force matching (AFM) has been developed that is capable of producing high quality force fields for condensed phase simulations. This procedure involves the parametrization of force fields to reproduce ab initio forces obtained from condensed phase quantum-mechanics/molecular-mechanics (QM/MM) calculations. During the procedure, the MM part of the QM/MM is iteratively improved so as to approach ab initio quality. In this work, the AFM method has been tested to parametrize force fields for liquid water so that the resulting force fields reproduce forces calculated using the ab initio MP2 and the Kohn-Sham density functional theory with the Becke-Lee-Yang-Parr (BLYP) and Becke three-parameter LYP (B3LYP) exchange correlation functionals. The AFM force fields generated in this work are very simple to evaluate and are supported by most molecular dynamics (MD) codes. At the same time, the quality of the forces predicted by the AFM force fields rivals that of very expensive ab initio calculations and are found to successfully reproduce many experimental properties. The site-site radial distribution functions (RDFs) obtained from MD simulations using the force field generated from the BLYP functional through AFM compare favorably with the previously published RDFs from Car-Parrinello MD simulations with the same functional. Technical aspects of AFM such as the optimal QM cluster size, optimal basis set, and optimal QM method to be used with the AFM procedure are discussed in this paper.     

Parameterization of OPLS-AA force field for the conformational analysis of macrocyclic polyketides

The parameters for the OPLS-AA potential energy function have been extended to include some functional groups that are present in macrocyclic polyketides. Existing OPLS-AA torsional parameters for alkanes, alcohols, ethers, hemiacetals, esters, and ketoamides were improved based on MP2/aug-cc-pVTZ and MP2/aug-cc-pVDZ calculations. Nonbonded parameters for the sp(3) carbon and oxygen atoms were refined using Monte Carlo simulations of bulk liquids. The resulting force field predicts conformer energies and torsional barriers of alkanes, alcohols, ethers, and hemiacetals with an overall RMS deviation of 0.40 kcal/mol as compared to reference data. Densities of 19 bulk liquids are predicted with an average error of 1.1%, and heats of vaporization are reproduced within 2.4% of experimental values. The force field was used to perform conformational analysis of smaller analogs of the macrocyclic polyketide drug FK506. Structures that adopted low-energy conformations similar to that of bound FK506 were identified. The results show that a linker of four ketide units constitutes the shortest effector domain that allows binding of the ketide drugs to FKBP proteins. It is proposed that the exact chemical makeup of the effector domain has little influence on the conformational preference of tetraketides.     

Automatic molecular structure perception for the universal force field

The Universal Force Field (UFF) is a classical force field applicable to almost all atom types of the periodic table. Such a flexibility makes this force field a potential good candidate for simulations involving a large spectrum of systems and, indeed, UFF has been applied to various families of molecules. Unfortunately, initializing UFF, that is, performing molecular structure perception to determine which parameters should be used to compute the UFF energy and forces, appears to be a difficult problem. Although many perception methods exist, they mostly focus on organic molecules, and are thus not well‐adapted to the diversity of systems potentially considered with UFF. In this article, we propose an automatic perception method for initializing UFF that includes the identification of the system's connectivity, the assignment of bond orders as well as UFF atom types. This perception scheme is proposed as a self‐contained UFF implementation integrated in a new module for the SAMSON software platform for computational nanoscience ( http://www.samson-connect.net ). We validate both the automatic perception method and the UFF implementation on a series of benchmarks.     

All‐atom polarizable force field for DNA based on the classical drude oscillator model

Presented is a first generation atomistic force field (FF) for DNA in which electronic polarization is modeled based on the classical Drude oscillator formalism. The DNA model is based on parameters for small molecules representative of nucleic acids, including alkanes, ethers, dimethylphosphate, and the nucleic acid bases and empirical adjustment of key dihedral parameters associated with the phosphodiester backbone, glycosidic linkages, and sugar moiety of DNA. Our optimization strategy is based on achieving a compromise between satisfying the properties of the underlying model compounds in the gas phase targeting quantum mechanical (QM) data and reproducing a number of experimental properties of DNA duplexes in the condensed phase. The resulting Drude FF yields stable DNA duplexes on the 100‐ns time scale and satisfactorily reproduce (1) the equilibrium between A and B forms of DNA and (2) transitions between the BI and BII substates of B form DNA. Consistency with the gas phase QM data for the model compounds is significantly better for the Drude model as compared to the CHARMM36 additive FF, which is suggested to be due to the improved response of the model to changes in the environment associated with the explicit inclusion of polarizability. Analysis of dipole moments associated with the nucleic acid bases shows the Drude model to have significantly larger values than those present in CHARMM36, with the dipoles of individual bases undergoing significant variations during the MD simulations. Additionally, the dipole moment of water was observed to be perturbed in the grooves of DNA. © 2014 Wiley Periodicals, Inc.     

A polarizable ellipsoidal force field for halogen bonds

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.     

Accurate van der Waals force field for gas adsorption in porous materials

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.     

Methodology for the calculation of the potential of mean force for a cation-pi complex in water.

We report potential of mean force (PMF) calculations on the interaction between the p-sulfonatocalix[4]arene and a monovalent cation (Cs(+)). It has been recently shown from microcalorimetry and (133)Cs NMR experiments that the association with Cs(+) is governed by favourable cation-pi interactions and is characterized by the insertion of the cation into the cavity of the macrocycle. We show that the PMF calculation based upon a classical model is not able to reproduce both the thermodynamic properties of association and the insertion of the cation. In order to take into account the different contributions of the cation-pi interactions, we develop a new methodology consisting of changing the standard PMF by an additional contribution resulting from quantum calculations. The calculated thermodynamic properties of association are thus in line with the microcalorimetry and (133)Cs NMR experiments and the structure of the complex at the Gibbs free-energy minimum shows the insertion of the cation into the cavity of the calixarene.     

Flexible matching of test ligands to a 3D pharmacophore using a molecular superposition force field: Comparison of predicted and experimental conformations of inhibitors of three enzymes

Summary A computer procedure TFIT, which uses a molecular superposition force field to flexibly match test compounds to a 3D pharmacophore, was evaluated to find out whether it could reliably predict the bioactive conformations of flexible ligands. The program superposition force field optimizes the overlap of those atoms of the test ligand and template that are of similar chemical type, by applying an attractive force between atoms of the test ligand and template which are close together and of similar type (hydrogen bonding, charge, hydrophobicity). A procedure involving Monte Carlo torsion perturbations, followed by torsional energy minimization, is used to find conformations of the test ligand which cominimize the internal energy of the ligand and the superposition energy of ligand and template. The procedure was tested by applying it to a series of flexible ligands for which the bioactive conformation was known experimentally. The 15 molecules tested were inhibitors of thermolysin, HIV-1 protease or endothiapepsin for which X-ray structures of the bioactive conformation were available. For each enzyme, one of the molecules served as a template and the others, after being conformationally randomized, were fitted. The fitted conformation was then compared to the known binding geometry. The matching procedure was successful in predicting the bioactive conformations of many of the structures tested. Significant deviation from experimental results was found only for parts of molecules where it was readily apparent that the template did not contain sufficient information to accurately determine the bioactive conformation.     

A polarizable force field for water using an artificial neural network

A force field for liquid water including polarization effects has been constructed using an artificial neural network (ANN). It is essential to include a many-body polarization effect explicitly into a potential energy function in order to treat liquid water which is dense and highly polar. The new potential energy function is a combination of empirical and nonempirical potentials. The TIP4P model was used for the empirical part of the potential. For the nonempirical part, an ANN with a back-propagation of error algorithm (BPNN) was introduced to reproduce the complicated many-body interaction energy surface from ab initio quantum mechanical calculations. BPNN, described in terms of a matrix, provides enough flexibility to describe the complex potential energy surface (PES). The structural and thermodynamic properties, calculated by isobaric-isothermal (constant-NPT) Monte Carlo simulations with the new polarizable force field for water, are compatible with experimental results. Thus, the simulation establishes the validity of using our estimated PES with a polarization effect for accurate predictions of liquid state properties. Applications of this approach are simple and systematic so that it can easily be applied to the development of other force fields besides the water-water system.     

Effect of cooperativity on the O-H stretching force constant in associated water species

CNDO/force calculations have been employed to calculate the O-H stretching force constants for various structures of associated water species such as water-dimethylether, water-acetonitrile, water-lithium fluoride, linear and cyclic water polymers. The variation in the O-H stretching force constant in A_m… O-H… D_n species where A_m and D_n represent, respectively,m number of electron-acceptor andn number of electron-donor molecules, is explained on the basis of the cooperativity effect. With increasing electron-acceptor power of A and electron-donor power of D, the hydrogen-bonded O-H stretching force constant is significantly reduced. The results obtained in these studies are in general agreement with experimental observations reported earlier.     

基于自适应蒙特卡洛法评定测量不确定度程序开发与应用

进行了基于自适应蒙特卡洛法评定测量不确定度的程序开发与应用。基于Python语言,设计开发自适应蒙特卡洛法评定测量不确定度程序,包含评定过程框架、自定义变量名称模块、过程参数关联计算模块以及蒙特卡洛法采样计算模块。程序界面简洁,操作简单,计算准确,适用于任意多个独立变量、任意多个过程参数及单一被测量的数学模型,为利用自适应蒙特卡洛法评定测量不确定度提供了方便。     

Molecular mechanics force field parameterization of the fluorescent probe rhodamine 6G using automated frequency matching

Novel single-molecule fluorescence experimental techniques have prompted a growing need to develop refined computational models of dye-tagged biomolecules. As a necessary first step towards useful molecular simulations of fluorescence-labeled biomolecules, we have derived a force field for the commonly used dye, rhodamine 6G (R6G). A novel automated method is used that includes fitting the molecular mechanics potential to both vibrational frequencies and eigenvector projections derived from quantum chemical calculations. The method is benchmarked on a series of aromatic molecules then applied to derive new parameters for R6G. The force field derived reproduces well the crystal structure of R6G.     

Ab initio protein structure prediction with force field parameters derived from water-phase quantum chemical calculation

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 alpha-helix and beta-sheet structures was significantly improved by the modification of charge parameters.