The parametrization and validation of the OPLS3 force field for small molecules proteins are reported. Enhancements with respect to previous version (OPLS2.1) include addition off-atom charge sites represent halogen bonding aryl nitrogen lone pairs as well a complete refit peptide dihedral parameters better model native structure proteins. To adequately cover medicinal chemical space, employs over an order magnitude more reference data associated parameter types relative other commonly used...

Jaguar is an ab initio quantum chemical program that specializes in fast electronic structure predictions for molecular systems of medium and large size. focuses on computational methods with reasonable scaling the size system, such as density functional theory (DFT) local second‐order Møller–Plesset perturbation theory. The favorable high efficiency make it possible to conduct routine computations involving several thousand orbitals. This performance achieved through a utilization...

We report on the development and validation of OPLS4 force field. builds upon our previous work with OPLS3e to improve model accuracy challenging regimes drug-like chemical space that includes molecular ions sulfur-containing moieties. A novel parametrization strategy for charged species, which can be extended other systems, is introduced. leads improved benchmarks assess small-molecule solvation protein–ligand binding.

Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chemical space by addressing limitations in chemotype transferability. OPLS3e accomplishes this incorporating new parameter types recognize moieties with greater specificity and integrating on-the-fly parametrization approach to assignment partial charges. As a consequence, leads accuracy against performance benchmarks assess small molecule conformational...

An accurate representation of ion solvation in aqueous solution is critical for meaningful computer simulations a broad range physical and biological processes. Polarizable models based on classical Drude oscillators are introduced parametrized large set monoatomic ions including cations the alkali metals (Li(+), Na(+), K(+), Rb(+) Cs(+)) alkaline earth elements (Mg(2+), Ca(2+), Sr(2+) Ba(2+)) along with Zn(2+) halide anions (F(-), Cl(-), Br(-) I(-)). The parameterized, conjunction...

Although many popular docking programs include a facility to account for covalent ligands, large-scale systematic validation studies of inhibitors have been sparse. In this paper, we present the development and novel approach scoring inhibitors, which consists conventional noncovalent docking, heuristic formation attachment point, structural refinement protein–ligand complex. This combines strengths program Glide protein structure modeling Prime does not require any parameter fitting study...

We propose a general methodology for calculating the self-diffusion tensor from molecular dynamics (MD) liquid with liquid−gas or liquid−solid interface. The standard method used in bulk fluids, based on computing mean square displacement as function of time and extracting asymptotic linear dependence this, is not valid systems interfaces confined fluids. proposed here imposing virtual boundary conditions system survival probabilities specified correlation functions different layers fluid up...

A principal goal of drug discovery project is to design molecules that can tightly and selectively bind the target protein receptor. Accurate prediction protein-ligand binding free energies therefore central importance in computational chemistry computer aided design. Multiple recent improvements computing power, classical force field accuracy, enhanced sampling methods, simulation setup have enabled accurate reliable calculations protein-ligands energies, position energy play a guiding role...

Explicit solvent molecular dynamics free energy perturbation simulations were performed to predict absolute solvation energies of 239 diverse small molecules. We use OPLS2.0, the next generation OPLS force field, and compare results with popular molecule fields-OPLS_2005, GAFF, CHARMm-MSI. OPLS2.0 produces best correlation experimental data (R(2) = 0.95, slope 0.96) lowest average unsigned errors (0.7 kcal/mol). Important classes compounds that suboptimally OPLS_2005 show significant improvements.

Computational techniques can speed up the identification of hits and accelerate development candidate molecules for drug discovery. Among predicting relative binding affinities, most consistently accurate is free energy perturbation (FEP), a class rigorous physics-based methods. However, uncertainty remains about how FEP ever be. Here, we present what believe to be largest publicly available dataset proteins congeneric series small molecules, assess accuracy leading workflow. To ascertain...

A polarizable force field of saturated phosphatidylcholine-containing lipids based on the classical Drude oscillator model is optimized and used in molecular dynamics simulations bilayer monolayer membranes. The hierarchical parametrization strategy involves optimization parameters for small molecules representative lipid functional groups, followed by their application larger compounds full lipids. polar headgroup ions tetramethyl ammonium dimethyl phosphate, esterified glycerol backbone...

Molecular dynamics (MD) simulations are used to investigate the properties of an atomic model aromatic polyamide reverse osmosis membrane. The monomers forming polymeric membrane cross-linked progressively on basis a heuristic distance criterion during MD until system interconnectivity reaches completion. Equilibrium hydrated then determine density and diffusivity water within Given 3 MPa pressure differential 0.125 μm width membrane, simulated flux is calculated be 1.4 × 10−6 m/s, which in...

The rapid growth of structural information for G-protein-coupled receptors (GPCRs) has led to a greater understanding their structure, function, selectivity, and ligand binding. Although novel ligands have been identified using methods such as virtual screening, computationally driven lead optimization possible only in isolated cases because challenges associated with predicting binding free energies related compounds. Here, we provide systematic characterization the performance free-energy...

The prediction of protein–ligand binding affinities using free energy perturbation (FEP) is becoming increasingly routine in structure-based drug discovery. Most FEP packages use molecular dynamics (MD) to sample the configurations proteins and ligands, as MD well-suited capturing coupled motion. However, can be prohibitively inefficient at sampling water molecules that are buried within sites, which has severely limited domain applicability its prospective usage In this paper, we present an...

Electron pairs in the valence shell of an atom that do not participate bonding a molecule ("lone pairs") give rise to concentrated electron density away from center. To account for asymmetry charge arises lone pairs, electrostatic model is developed parametrically anisotropic at atomic level. The uses virtual interaction sites with partial charges are associated but coincident nuclei. In addition, incorporates polarizabilities. protocol previously outlined Anisimov et al. [J. Chem. Theory...

Hydrogen-bond (H-bond) dynamics in the air−water interface is studied by molecular simulations. The analysis reveals that of breaking and forming hydrogen bonds faster than bulk water for polarizable models. This contrast to results found on a protein surface. We show difference stems from more rapid translational diffusion interface. When effect pair eliminated, hydrogen-bond observed be slower bulk. occurs because number molecules adjacent hydrogen-bonded available accept or donate bond...

The role played by electronic polarization in the dielectric properties of liquid N-methyl acetamide (NMA) is examined using molecular dynamics simulations with a polarizable force field based on classical Drude oscillators. model presented first shown to reproduce anomalously large constant NMA. Details polarizability are found be important. For instance, all elements tensor, rather then just trace, impact condensed phase properties. Two factors related contribute this constant. First...

Molecular dynamics simulations of a lipid monolayer at water−air interface are used to investigate the dipole potential that arises water−lipid interface. One simulation explicitly accounts for many-body polarization effects by using model based on classical Drude oscillators. The is 0.35V in excellent agreement with experimental estimates range between 0.3 and 0.4V, whereas, nonpolarizable significantly overestimates calculated value 0.8V. Induced nonpolar region found buffer residual...

The microscopic origin of the interface potential calculated from computer simulations is elucidated by considering a simple model molecules near an interface. posits that are isotropically oriented and their charge density Gaussian distributed. Molecules have more negative toward interior tend to give rise relative gaseous phase, while densities positive potential. for compared computed molecular dynamics nonpolar vacuum-methane system polar vacuum-water system. simulation (−220 mV)...

Recent advances in improved force fields and sampling methods have made it possible for the accurate calculation of protein–ligand binding free energies. Alchemical energy perturbation (FEP) using an explicit solvent model is one most rigorous to calculate relative However, cases where there are high barriers separating relevant conformations that important ligand binding, calculated may depend on initial conformation used simulation due lack complete all regions phase space. This...

Transferable high dimensional neural network potentials (HDNNPs) have shown great promise as an avenue to increase the accuracy and domain of applicability existing atomistic force fields for organic systems relevant life science. We previously reported such a potential (Schrödinger-ANI) that has broad coverage druglike molecules. extend work here cover ionic zwitterionic molecules expected be drug discovery research activities. report novel HDNNP architecture, which we call QRNN, predicts...

The particle–particle particle–mesh (P3M) method for calculating long-range electrostatic forces in molecular simulations is modified and combined with the reversible reference system propagator algorithm (RESPA) treating multiple time scale problems dynamics of complex systems scales forces. resulting Ewald RESPA (P3ME/RESPA) provides a fast accurate representation interactions biomolecular such as protein solutions. presented here uses different breakup than was used by other authors when...