The helix-coil transition for several alanine-rich alpha-helices with varying lengths was interrogated through adaptive steered molecular dynamic (ASMD) simulations, an enhanced sampling for obtaining observables along the unfolding pathway much more efficiently than steered molecular dynamics (SMD). The potential of mean force (PMF) results and the hydrogen bonding profiles were obtained for three families of alpha- helices, including polyalanine peptides as a reference model system, the synthesized polypeptides Ac-Y(AEAAKA)kF-NH2 (EK peptides) and a natural α-helical peptide a2N (1–17). With the help of all-atom simulations, the detailed mechanism of the helix-coil transition across all of these small proteins was found to exhibit a correspondence in their properties with respect to the unraveling of the helices. Specifically, the energetics are additive with respect to the chain length along the unfolding process. Each alpha-helical contact of these alpha-helices was lost and turned into a 310-helical contact in a sequential manner, followed by the formation of random coil conformations. Moreover, polyProline II (pPII) helical structures were also increasingly adopted as the chains are stretched. We found that the backbone hydrogen bonds, rather than the types of residues or the length of peptides, appear to be the most important factor in the helix-coil transition. These findings also shed light on the folding/unfolding pathways, and the overall stability of the α-helix structure in proteins.

Helix-coil transition for various length helices through ASMD simulations

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