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

¹ Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland 21218, USA
² Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York, New York 10029, USA
³ Advanced Technology Centre, Tata Consultancy Services, Hyderabad, India

(RECEIVED August 10, 2004; FINAL REVISION September 3, 2004; ACCEPTED September 3, 2004)

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 determined 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.

Keywords: Solvation energy; conditional hydrophobic accessible surface area; CHASA; polyproline-II; coil library; probability density map

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041047005.

Reprint requests to: George D. Rose, Jenkins Department of Biophysics, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA; e-mail: grose{at}jhu.edu; fax: (410) 516-4118.

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