Reaction path study of conformational transitions in flexible systems: Applications to peptides

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Abstract
A new protocol to find minima and transition states in flexible systems is proposed. It is tested on alanine dipeptide (AD) with four minima and eight transition states and applied to a flexible molecule, isobutyryl–(ala)3–NH–methyl (IAN), the shortest peptide which can form a full helical turn. There were found 138 minima and 490 transition states for IAN. It is shown that the connectivity network between the minima is very dilute and composed of transitions localized on one or two neighboring amide units. Most of the transitions involve one or two dihedral flips. The reaction coordinate from an extended chain conformation to a helix follows a sequence of nonoverlapping rotations around bonds. The rotations along the reaction coordinates are such that the hard repulsions between different atoms are minimized but at the same time the hydrogen bonding and the electrostatic interactions are maximized. A melting-like transition which is associated with the sudden opening of a large number of hopping channels is identified between minima at approximately 5 kcal/mol above the lowest energy minimum. The calculated minima and transition states are used to construct a master equation for the two molecules. The vibrational spectrum of the N–H stretch as a function of time and temperature is finally calculated. It is demonstrated that time-dependent lineshape analysis can be a useful tool to investigate the properties of the large number of minima and the intervening transitions.

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