Ronald M. Levy

Integrated Modeling Program, Applied Chemical Theory (IMPACT)

We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high‐throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function.

AGBNP: An analytic implicit solvent model suitable for molecular dynamics simulations and high‐resolution modeling

We have developed an implicit solvent effective potential (AGBNP) that is suitable for molecular dynamics simulations and high‐resolution modeling. It is based on a novel implementation of the pairwise descreening Generalized Born model for the electrostatic component and a new nonpolar hydration free energy estimator. The nonpolar term consists of an estimator for the solute‐solvent van der Waals dispersion energy designed to mimic the continuum solvent solute‐solvent van der Waals interaction energy, in addition to a surface area term corresponding to the work of cavity formation. AGBNP makes use of a new parameter‐free algorithm to calculate the scaling coefficients used in the pairwise descreening scheme to take into account atomic overlaps. The same algorithm is also used to calculate atomic surface areas. We show that excellent agreement is achieved for the GB self‐energies and surface areas in comparison to accurate, but much more expensive, numerical evaluations. The parameter‐free approach used in AGBNP and the sensitivity of the AGBNP model with respect to large and small conformational changes makes the model suitable for high‐resolution modeling of protein loops and receptor sites as well as high‐resolution prediction of the structure and thermodynamics of protein‐ligand complexes. We present illustrative results for these kinds of benchmarks. The model is fully analytical with first derivatives and is computationally efficient. It has been incorporated into the IMPACT molecular simulation program.

The SGB/NP hydration free energy model based on the surface generalized born solvent reaction field and novel nonpolar hydration free energy estimators

The development and parameterization of a solvent potential of mean force designed to reproduce the hydration thermodynamics of small molecules and macromolecules aimed toward applications in conformation prediction and ligand binding free energy prediction is presented. The model, named SGB/NP, is based on a parameterization of the Surface Generalized Born continuum dielectric electrostatic model using explicit solvent free energy perturbation calculations and a newly developed nonpolar hydration free energy estimator motivated by the results of explicit solvent simulations of the thermodynamics of hydration of hydrocarbons. The nonpolar model contains, in addition to the more commonly used solvent accessible surface area term, a component corresponding to the attractive solute–solvent interactions. This term is found to be important to improve the accuracy of the model, particularly for cyclic and hydrogen bonding compounds. The model is parameterized against the experimental hydration free energies of a set of small organic molecules. The model reproduces the experimental hydration free energies of small organic molecules with an accuracy comparable or superior to similar models employing more computationally demanding estimators and/or a more extensive set of parameters.

Computer simulations of the dielectric properties of water: Studies of the simple point charge and transferrable intermolecular potential models

A series of very long molecular dynamics simulations has been completed for the rigid simple point charge (SPC) and transferrable intermolecular potential 4P (TIP4P) water models with reaction field boundary conditions. The dielectric constant corresponding to these models was evaluated in two ways: (1) by calculating the fluctuations in the mean square dipole moment of the system in the absence of an applied field and (2) by evaluating the polarization response of the system to an applied field. Consistent values for the dielectric constant are obtained by the two methods. For the TIP4P water model, the dielectric constant e0 is calculated to be ∼50 at 293 K, in agreement with previously published results. For the rigid SPC model, e0 is calculated to be ∼68 at 300 K and ∼59 at 350 K. The calculated dielectric constant is shown to be very sensitive to the way in which the truncation of long‐range forces is treated, although the short‐range liquid properties are insensitive to the truncation procedure. The...

Effect of anisotropy and anharmonicity on protein crystallographic refinement: An evaluation by molecular dynamics

Molecular dynamics simulations are employed to determine the errors introduced by anharmonicity and anisotropy in the structure and temperature factors obtained for proteins by refinement of X-ray diffraction data. Simulations (25 ps and 300 ps) of metmyoglobin are used to generate time-averaged diffraction data at 1.5 A resolution. The crystallographic restrained-parameter least-squares refinement program PROLSQ is used to refine models against these simulated data. The resulting atomic positions and isotropic temperature factors are compared with the average structure and fluctuations calculated directly from the simulations. It is found that significant errors in the atomic positions and fluctuations are introduced by the refinement, and that the errors increase with the magnitude of the atomic fluctuations. Of particular interest is the fact that the refinement generally underestimates the atomic motions. Moreover, while the actual fluctuations go up to a mean-square value of about 5 A2, the X-ray results never go above approximately 2 A2. This systematic deviation in the motional parameters appears to be due to the use of a single-site isotropic model for the atomic fluctuations. Many atoms have multiple peaks in their probability distribution functions. For some atoms, the multiple peaks are seen in difference electron density maps and it is possible to include these in the refinement as disordered residues. However, for most atoms the refinement fits only one peak and neglects the rest, leading to the observed errors in position and temperature factor. The use of strict stereochemical restraints is inconsistent with the average dynamical structure; nevertheless, refinement with tight restraints results in structures that are comparable to those obtained with loose restraints and better than those obtained with no restraints. The results support the use of tight stereochemical restraints, but indicate that restraints on the variation of temperature factors are too restrictive.

Gaussian fluctuation formula for electrostatic free‐energy changes in solution

Linear‐response theory is used to derive a microscopic formula for the free‐energy change of a solute‐solvent system in response to a change in the charge distribution of the solutes. The formula expresses the change in the solvent polarization energy as a quadratic function of the changes in the partial charges at the atomic centers of the solute atoms. The average electrostatic potential at the sites of the solute charges and the second moment of the fluctuations in the electrostatic potential at these sites enter as parameters in the formula. These parameters can be obtained from computer simulations of a reference system with fixed solute charges and the results then compared with explicit free‐energy simulations of the corresponding processes or with experiment. The formula provides a microscopic definition of the dielectric response function for the combined solute plus solvent system which can be related to standard formulas for the dielectric response. A simple numerical example involving a simula...

Comparative Performance of Several Flexible Docking Programs and Scoring Functions: Enrichment Studies for a Diverse Set of Pharmaceutically Relevant Targets

Virtual screening by molecular docking has become a widely used approach to lead discovery in the pharmaceutical industry when a high-resolution structure of the biological target of interest is available. The performance of three widely used docking programs (Glide, GOLD, and DOCK) for virtual database screening is studied when they are applied to the same protein target and ligand set. Comparisons of the docking programs and scoring functions using a large and diverse data set of pharmaceutically interesting targets and active compounds are carried out. We focus on the problem of docking and scoring flexible compounds which are sterically capable of docking into a rigid conformation of the receptor. The Glide XP methodology is shown to consistently yield enrichments superior to the two alternative methods, while GOLD outperforms DOCK on average. The study also shows that docking into multiple receptor structures can decrease the docking error in screening a diverse set of active compounds.

ON FINITE-SIZE EFFECTS IN COMPUTER SIMULATIONS USING THE EWALD POTENTIAL

We discuss the origin and relevance for computer simulations of a strong finite‐size effect that appears when using the Ewald summation formula. It can be understood as arising from a volume‐dependent shift of the potential in a finite, periodic box relative to the infinite volume limit. This shift is due to the fact that the ‘‘zero of energy’’ for a periodic system cannot be defined by letting the interacting particles be separated by an infinite distance; the correct definition corresponds to setting its k=0 Fourier mode to zero. The implications of this effect for computer simulations are discussed.

Diffusive langevin dynamics of model alkanes

Abstract The diffusive Langevin equation of motion is used to simulate the equilibrium for times up to 100 ns. Comparisons are made between the results obtained with an isolated molecule potential surface and with one modified to incorporate solvent effects.

Distinguishing native conformations of proteins from decoys with an effective free energy estimator based on the OPLS all-atom force field and the surface generalized born solvent model

Protein decoy data sets provide a benchmark for testing scoring functions designed for fold recognition and protein homology modeling problems. It is commonly believed that statistical potentials based on reduced atomic models are better able to discriminate native‐like from misfolded decoys than scoring functions based on more detailed molecular mechanics models. Recent benchmark tests on small data sets, however, suggest otherwise. In this work, we report the results of extensive decoy detection tests using an effective free energy function based on the OPLS all‐atom (OPLS‐AA) force field and the Surface Generalized Born (SGB) model for the solvent electrostatic effects. The OPLS‐AA/SGB effective free energy is used as a scoring function to detect native protein folds among a total of 48,832 decoys for 32 different proteins from Park and Levitts 4‐state‐reduced, Levitts local‐minima, Bakers ROSETTA all‐atom, and Skolnicks decoy sets. Solvent electrostatic effects are included through the Surface Generalized Born (SGB) model. All structures are locally minimized without restraints. From an analysis of the individual energy components of the OPLS‐AA/SGB energy function for the native and the best‐ranked decoy, it is determined that a balance of the terms of the potential is responsible for the minimized energies that most successfully distinguish the native from the misfolded conformations. Different combinations of individual energy terms provide less discrimination than the total energy. The results are consistent with observations that all‐atom molecular potentials coupled with intermediate level solvent dielectric models are competitive with knowledge‐based potentials for decoy detection and protein modeling problems such as fold recognition and homology modeling. Proteins 2002;48:404–422.