Helix-coil transition of PrP106-126: Molecular dynamic study

A set of 34 molecular dynamic (MD) simulations totaling 305 ns of simulatio n time of the prion protein-derived peptide PrP106-126 was performed with b oth explicit and implicit solvent models. The objective of these simulation s is to investigate the relative stability of the a-helical conformation of the peptide and the mechanism for conversion from the helix to a random-co il structure. At neutral pH, the wild-type peptide was found to lose its in itial helical structure very fast, within a few nanoseconds (ns) from the b eginning of the simulations. The helix breaks up in the middle and then unw inds to the termini. The spontaneous transition into the random coil struct ure is governed by the hydrophobic interaction between His(111) and Val(122 ). The A117V mutation, which is linked to GSS disease, was found to destabi lize the helix conformation of the peptide significantly, leading to a comp lete loss of helicity approximately 1 ns faster than in the wild-type. Furt hermore, the A117V mutant exhibits a different mechanism for helix-coil con version, wherein the helix begins to break up at the C-terminus and then gr adually to unwind towards the N-terminus. In most simulations, the mutation was found to speed up the conversion through an additional hydrophobic int eraction between Met(112) and the mutated residue Val(117), an interaction that did not exist in the wild-type peptide. Finally, the P-sheet conformat ion of the wild-type peptide was found to be less stable at acidic pH due t o a destabilization of the His(111)-Val(122), since at acidic pH this histi dine is protonated and is unlikely to participate in hydrophobic interactio n. (C) 2001 Wiley-Liss, Inc.