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

Calculations of the ensemble of solution conformations and thermodynamics o f an analogue of the C-terminal helix of ribonuclease A (RN24) and of a syn thetic, beta-hairpin forming peptide (BH8) are presented. For efficient sam pling of conformation space, molecular dynamics simulations with an implici t solvent potential and umbrella sampling of the potential energy are perfo rmed. Starting from the fully extended chains, the simulations yield severa l folding and unfolding transitions between disordered (coil) conformations of the peptides and the "native" state (RN24, helix; BH8, hairpin); the si mulations also lead to the occurrence of "mis-folded" conformations (RN24, hairpin; BH8, helix). In agreement with experiment, the calculations predic t 58% helix for RN24 at 275 K and an antiparallel-beta content of 38% at 27 5 K for BH8; the calculated probabilities for the misfolded species ape 2% or smaller at all temperatures considered (250-1100 K). Good agreement is a lso shown between the calculated (3)J(HN alpha) spin-spin coupling constant s 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-hair pin (b), and coil (c), the free energy differences between the structured s ubstates are Delta G(ch) = G(c) - G(h) similar or equal to 1 kcal/mol and D elta 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 al pha to beta transition that is thought to play a role in amyloid fibril for mation. (C) 1998 Academic Press.