Reaction path study of helix formation in tetrapeptides: Effect of side chains

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Abstract
A computational protocol to calculate steepest descent paths in flexible molecules is discussed in detail. The algorithm does not use second derivatives and related matrices, and is therefore suitable for large systems. The shortest reaction coordinate from the helix to the extended chain conformation is calculated for a series of different tetrapeptides. The formation of a helical turn is investigated as a function of side chain properties. The known reaction coordinate for isobutyryl-ala3 -NH-methyl is employed as a starting guess in path calculations for six different tetrapeptides. The main results are: (i) χ1 (the side chain orientation angle) does not change significantly along the reaction coordinate. Alternative static values of χ1 (60,−60) significantly affect the size of the energy barrier (≊3 kcal/mol for valine). (ii) The mechanism for the transition is similar in all the peptides examined and is based on sequential flips of backbone torsions (Ψ dihedral angles). (iii) The energy barrier which is associated with the flip of Ψi is primarily determined by the side chain of residue i. Since the barriers for χ1 transitions are comparable to the barriers for conformational transitions in the backbone, the energetics of the helix formation is strongly affected by the side chain orientation angle. As a general conclusion, the side chain orientation angle affects more strongly the transition states than energy minima.