S. Roy Kimura

Bio: S. Roy Kimura is an academic researcher from Boston University. The author has contributed to research in topics: Solvation & Fourier transform. The author has an hindex of 4, co-authored 6 publications receiving 255 citations.

Scoring docked conformations generated by rigid-body protein-protein docking.

Abstract: Rigid-body methods, particularly Fourier correlation techniques, are very efficient for docking bound (co-crystallized) protein confor- mations using measures of surface complementar- ity as the target function. However, when docking unbound (separately crystallized) conformations, the method generally yields hundreds of false posi- tive structures with good scores but high root mean square deviations (RMSDs). This paper describes a two-step scoring algorithm that can discriminate near-native conformations (with less than 5 A RMSD) from other structures. The first step includes two rigid-body filters that use the desolvation free en- ergy and the electrostatic energy to select a manage- able number of conformations for further process- ing, but are unable to eliminate all false positives. Complete discrimination is achieved in the second step that minimizes the molecular mechanics en- ergy of the retained structures, and re-ranks them with a combined free-energy function which in- cludes electrostatic, solvation, and van der Waals energy terms. After minimization, the improved fit in near-native complex conformations provides the free-energy gap required for discrimination. The algorithm has been developed and tested using docking decoys, i.e., docked conformations gener- ated by Fourier correlation techniques. The decoy sets are available on the web for testing other discrimination procedures. Proteins 2000;40:525-537.

Surface of active polarons: A semiexplicit solvation method for biomolecular dynamics

Abstract: We present a strategy for solvating biomolecules in molecular dynamics or Monte Carlo simulations. The method employs a thin layer (often monomolecular) of explicit water with additional external forces representing the electrostatics, pressure, fluctuations, and dissipations caused by the neglected bulk. Long-range electrostatic corrections are supplied through a set of variable surface charges (polarons) that recreates the mean reaction field (or dielectric properties) of an infinite solvent. We refer to this “fictitious” boundary layer as a “surface of active polarons” (or SOAP). Test simulations of the solvation free energies of 15 amino acid analogs and nine ions are in good agreement with experiment (correlation coefficients: 0.995 and 1.000, respectively) despite the use of unaltered published force-fields with only one adjustable parameter. Dynamical capabilities of SOAP are illustrated by application to a six residue peptide with a stable conformation (SYPFDV), as well as a flexible nine residue HIV-1 gp120 peptide (TLTSCNTSV from PDB 1hhg). Future extensions, calibrations, and applications are discussed briefly.

The waters of life

Abstract: Water serves as a critical solvent for a remarkable array of molecules; in particular it profoundly influences the structure and activity of proteins, and their molecular interactions. Our ability to understand biological processes and to develop innovative applications for biotechnology depend in large part on understanding the biophysics of proteins in their solvated environment. The main difficulty in understanding solvation phenomena arises from the effects of electrostatics in complex biomolecular systems. In this paper we survey and critique the fundamental concepts and methodologies in evaluating electrostatic contributions to solvation.

Fourier Acceleration of Langevin Molecular Dynamics

Abstract: Fourier acceleration has been successfully applied to the simulation of lattice field theories for more than a decade. In this paper, we extend the method to the dynamics of discrete particles moving in a continuum. Although our method is based on a mapping of the particles' dynamics to a regular grid so that discrete Fourier transforms may be taken, it should be emphasized that the introduction of the grid is a purely algorithmic device and that no smoothing, coarse-graining, or mean-field approximations are made. The method thus can be applied to the equations of motion of molecular dynamics (MD) or its Langevin or Brownian variants. For example, in Langevin MD simulations our acceleration technique permits a straightforward spectral decomposition of forces so that the long-wavelength modes are integrated with a longer time step, thereby reducing the time required to reach equilibrium or to decorrelate the system in equilibrium. Speedup factors of up to 30 are observed relative to pure (unaccelerated) Langevin MD. As with acceleration of critical lattice models, even further gains relative to the unaccelerated method are expected for larger systems. Preliminary results for Fourier-accelerated molecular dynamics are presented in order to illustrate the basic concepts. Possible extensions of the method and further lines of research are discussed.

PatchDock and SymmDock: servers for rigid and symmetric docking

Abstract: Here, we describe two freely available web servers for molecular docking. The PatchDock method performs structure prediction of protein-protein and protein-small molecule complexes. The SymmDock method predicts the structure of a homomultimer with cyclic symmetry given the structure of the monomeric unit. The inputs to the servers are either protein PDB codes or uploaded protein structures. The services are available at http://bioinfo3d.cs.tau.ac.il. The methods behind the servers are very efficient, allowing large-scale docking experiments.

ZDOCK: An initial-stage protein-docking algorithm

Abstract: The development of scoring functions is of great importance to protein docking. Here we present a new scoring function for the initial stage of unbound docking. It combines our recently developed pairwise shape complementarity with desolvation and electrostatics. We compare this scoring function with three other functions on a large benchmark of 49 nonredundant test cases and show its superior performance, especially for the antibody-antigen category of test cases. For 44 test cases (90% of the benchmark), we can retain at least one near-native structure within the top 2000 predictions at the 6 degrees rotational sampling density, with an average of 52 near-native structures per test case. The remaining five difficult test cases can be explained by a combination of poor binding affinity, large backbone conformational changes, and our algorithm's strong tendency for identifying large concave binding pockets. All four scoring functions have been integrated into our Fast Fourier Transform based docking algorithm ZDOCK, which is freely available to academic users at http://zlab.bu.edu/~ rong/dock.

Principles of docking: An overview of search algorithms and a guide to scoring functions

Abstract: The docking field has come of age. The time is ripe to present the principles of docking, reviewing the current state of the field. Two reasons are largely responsible for the maturity of the computational docking area. First, the early optimism that the very presence of the "correct" native conformation within the list of predicted docked conformations signals a near solution to the docking problem, has been replaced by the stark realization of the extreme difficulty of the next scoring/ranking step. Second, in the last couple of years more realistic approaches to handling molecular flexibility in docking schemes have emerged. As in folding, these derive from concepts abstracted from statistical mechanics, namely, populations. Docking and folding are interrelated. From the purely physical standpoint, binding and folding are analogous processes, with similar underlying principles. Computationally, the tools developed for docking will be tremendously useful for folding. For large, multidomain proteins, domain docking is probably the only rational way, mimicking the hierarchical nature of protein folding. The complexity of the problem is huge. Here we divide the computational docking problem into its two separate components. As in folding, solving the docking problem involves efficient search (and matching) algorithms, which cover the relevant conformational space, and selective scoring functions, which are both efficient and effectively discriminate between native and non-native solutions. It is universally recognized that docking of drugs is immensely important. However, protein-protein docking is equally so, relating to recognition, cellular pathways, and macromolecular assemblies. Proteins function when they are bound to other molecules. Consequently, we present the review from both the computational and the biological points of view. Although large, it covers only partially the extensive body of literature, relating to small (drug) and to large protein-protein molecule docking, to rigid and to flexible. Unfortunately, when reviewing these, a major difficulty in assessing the results is the non-uniformity in the formats in which they are presented in the literature. Consequently, we further propose a way to rectify it here.

ClusPro: an automated docking and discrimination method for the prediction of protein complexes

Abstract: Motivation: Predicting protein interactions is one of the most challenging problems in functional genomics. Given two proteins known to interact, current docking methods evaluate billions of docked conformations by simple scoring functions, and in addition to near-native structures yield many false positives, i.e. structures with good surface complementarity but far from the native. Results: We have developed a fast algorithm for filtering docked conformations with good surface complementarity, and ranking them based on their clustering properties. The free energy filters select complexes with lowest desolvation and electrostatic energies. Clustering is then used to smooth the local minima and to select the ones with the broadest energy wells---a property associated with the free energy at the binding site. The robustness of the method was tested on sets of 2000 docked conformations generated for 48 pairs of interacting proteins. In 31 of these cases, the top 10 predictions include at least one near-native complex, with an average RMSD of 5 A from the native structure. The docking and discrimination method also provides good results for a number of complexes that were used as targets in the Critical Assessment of PRedictions of Interactions experiment. Availability: The fully automated docking and discrimination server ClusPro can be found at http://structure.bu.edu