Development of a computational prediction method based on molecular modeling, global optimization, and implicit solvation has produced accurate structure and relative binding affinity predictions for peptide amino acids binding to five pockets of the MHC molecule HLA-DRB1*0101. Because peptide binding to MHC molecules is essential to many immune responses, development of such a method for understanding and predicting the forces that drive binding is crucial for pharmaceutical design and disease treatment. Underlying the development of this prediction method are two hypotheses. The first is that pockets formed by the peptide binding groove of MHC molecules are independent, separating the prediction of peptide amino acids that bind within individual pockets from those that bind between pockets. The second hypothesis is that the native state of a system composed of an amino acid bound to a protein pocket corresponds to the system's lowest free energy. The prediction method developed from these hypotheses uses atomistic-level modeling, deterministic global optimization, and three methods of implicit solvation: solvent-accessible area, solvent-accessible volume, and Poisson–Boltzmann electrostatics. The method predicts relative binding affinities of peptide amino acids for pockets of HLA-DRB1*0101 by determining computationally an amino acid's global minimum energy conformation. Prediction results from the method are in agreement with X-ray crystallography data and experimental binding assays. Proteins 2004;54:000–000. © 2003 Wiley-Liss, Inc.
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