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Simulating the dielectric spectra of solvents requires the nuanced definition of inter- and intra-molecular forces. Non-polarizable force fields, while thoroughly benchmarked for dielectric applications, do not capture all the spectral features of solvents, such as water. Conversely, polarizable force fields have been largely untested in the context of dielectric spectroscopy but include charge and dipole fluctuations that contribute to intermolecular interactions. We benchmark non-polarizable force fields and the polarizable force fields AMOEBA03 and HIPPO for liquid water and find that the polarizable force fields can capture all the experimentally observed spectral features with varying degrees of accuracy. However, the non-polarizable force fields miss at least one peak. To diagnose this deficiency, we decompose the liquid water spectra from polarizable force fields at multiple temperatures into static and induced dipole contributions and find that the peak originates from induced dipole contributions. Broadening our inquiry to other solvents parameterized with the AMOEBA09 force field, we demonstrate good agreement between the experimental and simulated dielectric spectra of methanol and formamide. To produce these spectra, we develop a new computational approach to calculate the dielectric spectrum via the fluctuation dissipation theorem. This method minimizes the error in both the low and high frequency portions of the spectrum, improving the overall accuracy of the simulated spectrum and broadening the computed frequency range. [ABSTRACT FROM AUTHOR]

Force Field X (FFX) is an open-source software package for atomic resolution modeling of genetic variants and organic crystals that leverages advanced potential energy functions and experimental data. FFX currently consists of nine modular packages with novel algorithms that include global optimization via a many-body expansion, acid–base chemistry using polarizable constant-pH molecular dynamics, estimation of free energy differences, generalized Kirkwood implicit solvent models, and many more. Applications of FFX focus on the use and development of a crystal structure prediction pipeline, biomolecular structure refinement against experimental datasets, and estimation of the thermodynamic effects of genetic variants on both proteins and nucleic acids. The use of Parallel Java and OpenMM combines to offer shared memory, message passing, and graphics processing unit parallelization for high performance simulations. Overall, the FFX platform serves as a computational microscope to study systems ranging from organic crystals to solvated biomolecular systems. [ABSTRACT FROM AUTHOR]

Accurate modeling of intermolecular repulsion is an integral component in force field development. Although repulsion can be explicitly calculated by applying the Pauli exclusion principle, this approach is computationally viable only for systems of limited sizes. Instead, it has previously been shown that repulsion can be reformulated in a "classical" picture: the Pauli exclusion principle prohibits electrons from occupying the same state, leading to a depletion of electronic charge between atoms, giving rise to an enhanced nuclear–nuclear electrostatic repulsion. This classical picture is called the isotropic S2/R approximation, where S is the overlap and R is the interatomic distance. This approximation accurately captures the repulsion of isotropic atoms such as noble gas dimers; however, a key deficiency is that it fails to capture the angular dependence of the repulsion of anisotropic molecules. To include directionality, the wave function must at least be a linear combination of s and p orbitals. We derive a new anisotropic S2/R repulsion model through the inclusion of the anisotropic p orbital term in the total wave function. Because repulsion is pairwise and decays rapidly, it can be truncated at a short range, making it amenable for efficient calculation of energy and forces in complex biomolecular systems. We present a parameterization of the S101 dimer database against the ab initio benchmark symmetry-adapted perturbation theory, which yields an rms error of only 0.9 kcal/mol. The importance of the anisotropic term is demonstrated through angular scans of water–water dimers and dimers involving halobenzene. Simulation of liquid water shows that the model can be computed efficiently for realistic system sizes. [ABSTRACT FROM AUTHOR]

Inositol polyphosphate 1-phosphatase (INPP1) is a prototype member of metal-dependent/lithium-inhibited phosphomonoesterase protein family defined by a conserved three-dimensional core structure. Enzymes within this family function in distinct pathways including inositide signaling, gluconeogenesis, and sulfur assimilation. Using structural and biochemical studies, we report the effect of substrate and lithium on a network of metal binding sites within the catalytic center of INPP1. We find that lithium preferentially occupies a key site involved in metal-activation only when substrate or product is added. Mutation of a conserved residue that selectively coordinates the putative lithium-binding site results in a dramatic 100-fold reduction in the inhibitory constant as compared with wild-type. Furthermore, we report the INPP1/inositol 1,4-bisphosphate complex which illuminates key features of the enzyme active site. Our results provide insights into a structural basis for uncompetitive lithium inhibition and substrate recognition and define a sequence motif for metal binding within this family of regulatory phosphatases.

Computational simulation of biomolecules can provide important insights into protein design, protein-ligand binding interactions, and ab initio biomolecular folding, among other applications. Accurate treatment of the solvent environment is essential in such applications, but the use of explicit solvents can add considerable cost. Implicit treatment of solvent effects using a dielectric continuum model is an attractive alternative to explicit solvation since it is able to describe solvation effects without the inclusion of solvent degrees of freedom. Previously, we described the development and parameterization of implicit solvent models for small molecules. Here, we extend the parameterization of the generalized Kirkwood (GK) implicit solvent model for use with biomolecules described by the AMOEBA force field via the addition of corrections to the calculation of effective radii that account for interstitial spaces that arise within biomolecules. These include element-specific pairwise descreening scale factors, a short-range neck contribution to describe the solvent-excluded space between pairs of nearby atoms, and finally tanh-based rescaling of the overall descreening integral. We then apply the AMOEBA/GK implicit solvent to a set of ten proteins and achieve an average coordinate root mean square deviation for the experimental structures of 2.0 Å across 500 ns simulations. Overall, the continued development of implicit solvent models will help facilitate the simulation of biomolecules on mechanistically relevant timescales. [ABSTRACT FROM AUTHOR]

Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC) architectures, such as multicore CPUs and modern graphics processing units (GPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware platforms. We have now approached an era where multipole-based polarizable force fields can be routinely used to obtain computational results comparable to state-of-the-art density functional theory while reaching sampling statistics that are acceptable when compared to that obtained from simpler fixed partial charge force fields.

A set of improved parameters for the AMOEBA polarizable atomic multipole water model is developed. An automated procedure, ForceBalance, is used to adjust model parameters to enforce agreement with ab initio-derived results for water clusters and experimental data for a variety of liquid phase properties across a broad temperature range. The values reported here for the new AMOEBA14 water model represent a substantial improvement over the previous AMOEBA03 model. The AMOEBA14 model accurately predicts the temperature of maximum density and qualitatively matches the experimental density curve across temperatures from 249 to 373 K. Excellent agreement is observed for the AMOEBA14 model in comparison to experimental properties as a function of temperature, including the second virial coefficient, enthalpy of vaporization, isothermal compressibility, thermal expansion coefficient, and dielectric constant. The viscosity, self-diffusion constant, and surface tension are also well reproduced. In comparison to high-level ab initio results for clusters of 2-20 water molecules, the AMOEBA14 model yields results similar to AMOEBA03 and the direct polarization iAMOEBA models. With advances in computing power, calibration data, and optimization techniques, we recommend the use of the AMOEBA14 water model for future studies employing a polarizable water model.

Molecular force fields have been approaching a generational transition over the past several years, moving away from well-established and well-tuned, but intrinsically limited, fixed point charge models toward more intricate and expensive polarizable models that should allow more accurate description of molecular properties. The recently introduced AMOEBA force field is a leading publicly available example of this next generation of theoretical model, but to date, it has only received relatively limited validation, which we address here. We show that the AMOEBA force field is in fact a significant improvement over fixed charge models for small molecule structural and thermodynamic observables in particular, although further fine-tuning is necessary to describe solvation free energies of drug-like small molecules, dynamical properties away from ambient conditions, and possible improvements in aromatic interactions. State of the art electronic structure calculations reveal generally very good agreement with AMOEBA for demanding problems such as relative conformational energies of the alanine tetrapeptide and isomers of water sulfate complexes. AMOEBA is shown to be especially successful on protein-ligand binding and computational X-ray crystallography where polarization and accurate electrostatics are critical.

Pauli repulsion is a key component of any theory of intermolecular interactions. Although Pauli or exchange repulsion has its origin in the quantum mechanical nature of electrons, it is possible to describe the resulting energetic effects via a classical model in terms of the overlap of electron densities. In fact, closed shell intermolecular repulsion can be explained as a diminution of election density in the internuclear region resulting in decreased screening of nuclear charges and increased nuclear-nuclear repulsion. We provide a concise anisotropic repulsion formulation using the atomic multipoles from the Atomic Multipole Optimized Energetics for Biomolecular Applications force field to describe the electron density at each atom in a larger system. Mathematically, the proposed model consists of damped pairwise exponential multipolar repulsion interactions truncated at short range, which are suitable for use in compute-intensive biomolecular force fields and molecular dynamics simulations. Parameters for 26 atom classes encompassing most organic molecules are derived from a fit to Symmetry Adapted Perturbation Theory exchange repulsion energies for the S101 dimer database. Several applications of the multipolar Pauli repulsion model are discussed, including noble gas interactions, analysis of stationary points on the water dimer potential surface, and the directionality of several halogen bonding interactions. [ABSTRACT FROM AUTHOR]

Accurate modeling of dispersion is critical to the goal of predictive biomolecular simulations. To achieve this accuracy, a model must be able to correctly capture both the short-range and asymptotic behavior of dispersion interactions. We present here a damped dispersion model based on the overlap of charge densities that correctly captures both regimes. The overlap damped dispersion model represents a classical physical interpretation of dispersion: the interaction between the instantaneous induced dipoles of two distinct charge distributions. This model is shown to be an excellent fit with symmetry adapted perturbation theory dispersion energy calculations, yielding an RMS error on the S101x7 database of 0.5 kcal/mol. Moreover, the damping function used in this model is wholly derived and parameterized from the electrostatic dipole-dipole interaction, making it not only physically grounded but transferable as well. [ABSTRACT FROM AUTHOR]

Many cutting edge force fields include polarization, to enhance their accuracy and range of applicability. In this work, we develop efficient strategies for the induced dipole polarization method. By fitting various orders of perturbation theory (PT) dipoles to a diverse training set, we arrive at a family of fully analytic methods -- whose nth order is referred to OPTn -- that span the full spectrum of polarization methods from the fast zeroth-order approach that neglects mutual dipole coupling, approaching the fully variational approach at high order. Our training set contains many difficult cases where the PT series diverges, and we demonstrate that our OPTn methods still deliver excellent results in these cases. Our tests show that the OPTn methods exhibit rapid convergence towards the exact answer with each increasing PT order. The fourth order OPT4 method, whose costs are commensurate with three iterations of the leading conjugate gradient method, is a particularly promising candidate to be used as a drop-in replacement for existing solvers without further parameterization. [ABSTRACT FROM AUTHOR]

AMOEBA is an atomic multippole-based model that treats dipole polarization explicitly. The parameters in this water model were derived from gas-phase and room temperature liquid properties, mainly the density and heat of vaporization. By comparing AMOEBA and a variant parameterization, AMOEBA-v, it is demonstrated that much of the anomalous behavior of water is closely related to its hydrogen bonding properties.

It is not possible to separate total solvation free energies of thermodynamic solvation of salts and electrolytes into distinct cation and anion contributions without reference to an additional extra thermodynamic assumptions. This is resolved by using molecular dynamics simulations with the AMOEBA polarizable force field and perturbation techniques.

A large superfamily of transmembrane receptors control cellular responses to diverse extracellular signals by catalyzing activation of specific types of heterotrimeric GTP-binding proteins. How these receptors recognize and promote nucleotide exchange on G protein [Alpha] subunits to initiate signal amplification is unknown. The three-dimensional structure of the transducin (Gt) [Alpha] subunit C-terminal undecapeptide Gt[Alpha](340-350) IKENLKDCGLF was determined by transferred nuclear Overhauser effect spectroscopy while it was bound to photoexcited rhodopsin. Light activation of rhodopsin causes a dramatic shift from a disordered conformation of Gt[Alpha](340-350) to a binding motif with a helical turn followed by an open reverse turn centered at Gly-348, a helix-terminating C capping motif of an [[Alpha].sub.L] type. Docking of the NMR structure to the GDP-bound x-ray structure of Gt reveals that photoexcited rhodopsin promotes the formation of a continuous helix over residues 325-346 terminated by the C-terminal helical cap with a unique cluster of crucial hydrophobic side chains. A molecular mechanism by which activated receptors can control G proteins through reversible conformational changes at the receptor-G protein interface is demonstrated.

The multiple isomorphous replacement method helps establish the crystal structure of recombinant bovine inositol polyphosphate 1-phosphatase (1-ptase), in the presence of Mg2+ at a resolution of 2.3 angstroms. 1-ptase exhibits monomerism and is alternatively folded into alpha/beta layers. The central core has a six-stranded antiparallel beta sheet with two perpendicular alpha-helices. Two antiparallel alpha-helices surround the beta sheet, while a five-stranded parallel beta sheet surrounds the central helices. The acidic pockets of the structure consist of two metal binding sites.

Modeling the change in the electrostatics of organic molecules upon moving from vacuum into solvent, due to polarization, has long been an interesting problem. In vacuum, experimental values for the dipole moments and polarizabilities of small, rigid molecules are known to high accuracy; however, it has generally been difficult to determine these quantities for a polar molecule in water. A theoretical approach introduced by Onsager [J. Am. Chem. Soc. 58, 1486 (1936)] used vacuum properties of small molecules, including polarizability, dipole moment, and size, to predict experimentally known permittivities of neat liquids via the Poisson equation. Since this important advance in understanding the condensed phase, a large number of computational methods have been developed to study solutes embedded in a continuum via numerical solutions to the Poisson-Boltzmann equation. Only recently have the classical force fields used for studying biomolecules begun to include explicit polarization in their functional forms. Here the authors describe the theory underlying a newly developed polarizable multipole Poisson-Boltzmann (PMPB) continuum electrostatics model, which builds on the atomic multipole optimized energetics for biomolecular applications (AMOEBA) force field. As an application of the PMPB methodology, results are presented for several small folded proteins studied by molecular dynamics in explicit water as well as embedded in the PMPB continuum. The dipole moment of each protein increased on average by a factor of 1.27 in explicit AMOEBA water and 1.26 in continuum solvent. The essentially identical electrostatic response in both models suggests that PMPB electrostatics offers an efficient alternative to sampling explicit solvent molecules for a variety of interesting applications, including binding energies, conformational analysis, and pKa prediction. Introduction of 150 mM salt lowered the electrostatic solvation energy between 2 and 13 kcal/mole, depending on the formal charge of the protein, but had only a small influence on dipole moments. [ABSTRACT FROM AUTHOR]

A new classical empirical potential proposed for water uses a polarizable atomic multiple description of electrostatic interactions. The results are obtained for numerous properties, including cluster structures and energetics and bulk thermodynamic and structural measures.

Presents general methods for calculating the reaction field generated by a set of off-center point multipoles in a spherical cavity. Generalization of Kirkwood's original theory for an arbitrary charge distribution; Incorporation of reaction field effects in computation of induced dipole moments; Use of reaction field energy terms with empirical potential energy functions.