Populations of the Minor α-Conformation in AcGXGNH(2) and the α-Helical Nucleation Propensities

Intrinsic backbone conformational preferences of different amino acids are important for understanding the local structure of unfolded protein chains. Recent evidence suggests α-structure is relatively minor among three major backbone conformations for unfolded proteins. The α-helices are the dominant structures in many proteins. For these proteins, how could the α-structures occur from the least in unfolded to the most in folded states? Populations of the minor α-conformation in model peptides provide vital information. Reliable determination of populations of the α-conformers in these peptides that exist in multiple equilibriums of different conformations remains a challenge. Combined analyses on data from AcGXPNH(2) and AcGXGNH(2) peptides allow us to derive the populations of PII, β and α in AcGXGNH(2). Our results show that on average residue X in AcGXGNH(2) adopt PII, β, and α 44.7%, 44.5% and 10.8% of time, respectively. The contents of α-conformations for different amino acids define an α-helix nucleation propensity scale. With derived PII, β and α-contents, we can construct a free energy-conformation diagram on each AcGXGNH(2) in aqueous solution for the three major backbone conformations. Our results would have broad implications on early-stage events of protein folding.