A novel method reveals that solvent water favors polyproline II over β-strand conformation in peptides and unfolded proteins: conditional hydrophobic accessible surface area (CHASA)

Patrick J. Fleming, Nicholas C. Fitzkee, Mihaly Mezei, Rajgopal Srinivasan, George D. Rose
2009 Protein Science  
In aqueous solution, the ensemble of conformations sampled by peptides and unfolded proteins is largely determined by their interaction with water. It has been a long-standing goal to capture these solute-water energetics accurately and efficiently in calculations. Historically, accessible surface area (ASA) has been used to estimate these energies, but this method breaks down when applied to amphipathic peptides and proteins. Here we introduce a novel method in which hydrophobic ASA is
more » ... ed after first positioning water oxygens in hydrogen-bonded orientations proximate to all accessible peptide/protein backbone N and O atoms. This conditional hydrophobic accessible surface area is termed CHASA. The CHASA method was validated by predicting the polyproline-II (P II ) and ␤-strand conformational preferences of non-proline residues in the coil library (i.e., non-␣-helix, non-␤-strand, non-␤-turn library derived from X-ray elucidated structures). Further, the method successfully rationalizes the previously unexplained solvation energies in polyalanyl peptides and compares favorably with published experimentally determined P II residue propensities. We dedicate this paper to Frederic M. Richards. Of the many factors that determine the conformation of polypeptides, the interaction with water is one of the most important. Intrapeptide backbone interactions limit available conformational space (Pappu and Rose 2002), and sidechain interactions specify conformational preferences (Chou and Fasman 1978; Creamer and Rose 1992; Penel and Doig 2001) , but neither works in isolation. Rather, such effects act in concert with solvation preferences, which are measured by the free energy of interaction between peptides and water (Luo and Baldwin 1999; Thomas et al. 2001) . It is often assumed, usually implicitly, that protein backbone solvation is uniform in the unfolded state. However, computational studies indicate that the solvation energetics differ among conformations in both peptides (Anderson and . Article published online ahead of print. Article and publication date are at
doi:10.1110/ps.041047005 pmid:15576559 pmcid:PMC2253334 fatcat:h4oe6pi2mvgtzj76azkxhzxnwi