Free Energy Surfaces of -Hairpin and -Helical Peptides Generated by Replica Exchange Molecular Dynamics with the AGBNP Implicit Solvent Model

We have studied the potential of mean force of two peptides, one known to adopt a -hairpin and the other an -helical conformation in solution. These peptides are, respectively, residues 41–56 of the C-terminus (GEWTYDDATKTFTVTE) of the B1 domain of protein G and the 13 residue C-peptide (KETAAAKFERQHM) of ribonuclease A. Extensive canonical ensemble sampling has been performedusing aparallel replica exchangemethod. The effective potential employed in this work consists of the OPLS all-atom force field (OPLS-AA) and an analytical generalized Born (AGB) implicit solvent model including a novel nonpolar solvation free energy estimator (NP). An additional dielectric screening parameter has been incorporated into the AGBNP model. In the case of the -hairpin, the nonpolar solvation free energy estimator provides the necessary effective interactions for the collapse of the hydrophobic core (W43, Y45, F52, and V54), which themore commonly used surface-area-dependent nonpolar model does not provide. For both the -hairpin and the -helix, increased dielectric screening reduces the stability of incorrectly formed salt bridges, which tend to disrupt the formation of the hairpin and helix, respectively. The fraction of -hairpin and -helix content we obtained using the AGBNP model agrees well with experimental results. The thermodynamic stability of the -hairpin from protein G and the -helical C-peptide from ribonuclease A as modeled with the OPLS-AA/ AGBNP effective potential reflects the balance between the nonpolar effective potential terms, which drive compaction, and the polar andhydrogen bonding terms, which promote secondary structure formation. Proteins 2004;56:310–321. © 2004Wiley-Liss, Inc.