Free energy surfaces of β‐hairpin and α‐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 β‐hairpin and the other an α‐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 performed using a parallel replica exchange method. 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 β‐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 the more commonly used surface‐area‐dependent nonpolar model does not provide. For both the β‐hairpin and the α‐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 β‐hairpin and α‐helix content we obtained using the AGBNP model agrees well with experimental results. The thermodynamic stability of the β‐hairpin from protein G and the α‐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 and hydrogen bonding terms, which promote secondary structure formation. Proteins 2004. © 2004 Wiley‐Liss, Inc.