TitleFast accurate evaluation of protein solvent exposure.
Publication TypeJournal Article
Year of Publication2004
AuthorsZhang, N, Zeng, C, Wingreen, NS
Date Published2004 Nov 15
KeywordsComputational Biology, Databases, Protein, Drug Design, Protein Folding, Proteins, Research Design, Sensitivity and Specificity, Solvents, Surface Properties, Thermodynamics, Time Factors

Protein solvation energies are often taken to be proportional to solvent-accessible surface areas. Computation of these areas is numerically demanding and may become a bottleneck for folding and design applications. Fast graph-based methods, such as dead-end elimination (DEE), become possible if all energies, including solvation energies, are expressed as single-residue and pair-residue terms. To this end, Street and Mayo originated a pair-residue approximation for solvent-accessible surface areas (Street AG, Mayo SL. Pairwise calculation of protein solvent accessible surface areas. Fold Des 1998;3:253-258). The dominant source of error in this method is the overlapping burial of side-chain surfaces in the protein core. Here we report a new pair-residue approximation, which greatly reduces this overlap error by the use of optimized generic side-chains. We have tested the generic-side-chain method for the ten proteins studied by Street and Mayo and for 377 single-domain proteins from the CATH database (Orengo CA, Michie AD, Jones S, Jones DT, Swindells MB, Thornton JM. CATH-A hierarchic classification of protein domain structures. Structure 1997;5:1093-1108). With little additional cost in computation, the new method consistently reduces error for total areas and residue-by-residue areas by more than a factor of two. For example, the residue-by-residue error (for buried area) is reduced from 7.42 A(2) to 3.70 A(2). This difference translates into a solvation energy difference of approximately 0.2 kcal/mol per residue, amounting to a reduction in root-mean-square energy error of 2 kcal/mol for a 100 residue chain, a potentially critical difference for both protein folding and design applications.

Alternate JournalProteins