Solution conformations and thermodynamics of structured peptides: Molecular dynamics simulation with an implicit solvation model

Calculations of the ensemble of solution conformations and thermodynamics of an analogue of the C-terminal helix of ribonuclease A (RN24) and of a synthetic, beta-hairpin forming peptide (BH8) are presented. For efficient sampling of conformation space, molecular dynamics simulations with an implicit solvent potential and umbrella sampling of the potential energy are performed. Starting from the fully extended chains, the simulations yield several folding and unfolding transitions between disordered (coil) conformations of the peptides and the "native" state (RN24, helix; BH8, hairpin); the simulations also lead to the occurrence of "mis-folded" conformations (RN24, hairpin; BH8, helix). In agreement with experiment, the calculations predict 58% helix for RN24 at 275 K and an antiparallel-beta content of 38% at 275 K for BH8; the calculated probabilities for the misfolded species ape 2% or smaller at all temperatures considered (250-1100 K). Good agreement is also shown between the calculated (3)J(HN alpha) spin-spin coupling constants of RN24 and BH8 at 275 K, and those obtained from NMR experiments at the same temperature. From the calculated probabilities of helix (h), beta-hairpin (b), and coil (c), the free energy differences between the structured substates are Delta G(ch) = G(c) - G(h) similar or equal to 1 kcal/mol and Delta G(bh) greater than or equal to 1.8 kcal/mol for RN24, and Delta G(cb) similar or equal to 0.7 kcal/mol and Delta G(hb) greater than or equal to 2.7 kcal/mol for BH8. The free energy difference between "correctly" folded and misfolded secondary structures are of interest for understanding the alpha to beta transition that is thought to play a role in amyloid fibril formation. (C) 1998 Academic Press.