otease-protein inhibitor and four antibody-antigen complexes. A large number of putative docked complexes have already been generated for the test systems using our rigid-body docking program, FTDOCK. They include geometries that closely resemble the crystal complex, and therefore act as a test for the renement procedure. In the protease-inhibitors, geometries that resemble the crystal complex are ranked in the top four solutions for four out of ve systems when solvation is included in the energy function, against a background of between 26 and 364 complexes in the data set. The results for the antibody-antigen complexes are not as encouraging, with only two of the four systems showing discrimination. It would appear that these results reect the somewhat different binding mechanism dominant in the two types of protein-protein complex. Binding in the protease-inhibitors appears to be "lock and key" in nature. The xed backbone and mobile side-chain representation provide a good model for

Continuum solvation models, such as Poisson– Boltzmann and Generalized Born methods, have become increasingly popular tools for investigating the influence of electrostatics on biomolecular structure, energetics and dynamics. However, the use of such methods requires accurate and complete structural data as well as force field parameters such as atomic charges and radii. Unfortunately, the limiting step in continuum electrostatics calculations is often the addition of missing atomic coordinates to molecular structures from the Protein Data Bank and the assignment of parameters to biomolecular structures. To address this problem, we have developed the PDB2PQR web service

ABSTRACT A recently introduced real-space lattice methodology for solving the three-dimensional Poisson-Nernst-Planck equations is used to compute current-voltage relations for ion permeation through the gramicidin A ion channel embedded in membranes characterized by surface dipoles and/or surface charge. Comparisons to a variety of experimental results, presented herein, have proven largely successful. Strengths and weaknesses of the method are discussed.

A unifying principle of rational drug design is the use of either shape similarity or complementarity to identify compounds expected to be active against a given target. Shape similarity is the underlying foundation of ligand-based methods, which seek compounds with structure similar to known actives, while shape complementarity is the basis of most receptorbased

ABSTRACT A new program named “DARWIN” has been developed to perform docking calculations with proteins and other biological molecules. The program uses the Genetic Algorithm to optimize the molecule’s conformation and orientation under the selective pressure of minimizing the potential energy of the complex. A unique feature of DARWIN is that it communicates with the molecular mechanics program CHARMM to make the energy calculations. A second important feature is its parallel interface, which allows simultaneous use of multiple standalone copies of CHARMM to rapidly evaluate large numbers of potential solutions. This permits an “accuracy first ” approach to docking, which avoids many of the common assumptions and shortcuts often made to reduce computation time. The method was applied to three protein-carbohydrate complexes: the crystallographically determined structures of Concanavalin A and Fab Se155-4; and a model structure for Fab ME36.1. Conformations close to the crystal structures were obtained with this approach, but some “false positive ” solutions were also selected. Many of these could be eliminated by introducing different methods for simulating solvent effects. An effective screening method for docking a database of compounds to a single target enzyme using DARWIN is also presented. Proteins 2000;41:173–191. © 2000 Wiley-Liss, Inc. Key words: genetic algorithm; protein-ligand interaction; carbohydrate binding; antibodyantigen recognition; drug design

Energy functions for protein design I: Efficient and accurate

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Research article Statistical deconvolution of enthalpic energetic contributions to MHC-peptide binding affinity

Research article