PEDS Advance Access originally published online on September 9, 2005
Protein Engineering Design and Selection 2005 18(10):465-476; doi:10.1093/protein/gzi052
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Refinement of protein cores and protein–peptide interfaces using a potential scaling approach
1International University Bremen, School of Engineering and Science, D-28759 Bremen, Germany and 2Institut für Molekulare Biotechnologie, Beutenbergstrasse 11, D-07745 Jena, Germany
3 To whom correspondence should be addressed. E-mail: m.zacharias{at}iu-bremen.de
Refinement of side chain conformations in protein model structures and at the interface of predicted protein–protein or protein–peptide complexes is an important step during protein structural modelling and docking. A common approach for side chain prediction is to assume a rigid protein main chain for both docking partners and search for an optimal set of side chain rotamers to optimize the steric fit. However, depending on the target–template similarity in the case of comparative protein modelling and on the accuracy of an initially docked complex, the main chain template structure is only an approximation of a realistic target main chain. An inaccurate rigid main chain conformation can in turn interfere with the prediction of side chain conformations. In the present study, a potential scaling approach (PS-MD) during a molecular dynamics (MD) simulation that also allows the inclusion of explicit solvent has been used to predict side chain conformations on semi-flexible protein main chains. The PS-MD method converges much faster to realistic protein–peptide interface structures or protein core structures than standard MD simulations. Depending on the accuracy of the protein main chain, it also gives significantly better results compared with the standard rotamer search method.
Keywords: molecular dynamics simulation/peptide–protein docking/potential smoothing/protein design/side chain prediction
Received January 17, 2005; revised April 21, 2005; accepted July 11, 2005.
Edited by Fred Cohen
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