The potential of mean force (PMF) for stretching decaalanine in vacuum was determined earlier by Park and Schulten [J. Chem. Phys. 120, 5946 (2004)] in a landmark article demonstrating the efficacy of combining steered molecular dynamics and Jarzynski's nonequilibrium relation. In this study, the recently developed adaptive steered molecular dynamics (ASMD) algorithm [G. Ozer, E. Valeev, S. Quirk, and R. Hernandez, J. Chem. Theory Comput. 6, 3026 (2010)] is used to reproduce the PMF of the unraveling of decaalanine in vacuum by averaging over fewer nonequilibrium trajectories. The efficiency and accuracy of the method are demonstrated through the agreement with the earlier work by Park and Schulten, a series of convergence checks compared to alternate SMD pulling strategies, and an analytical proof. The nonequilibrium trajectories obtained through ASMD have also been used to analyze the intrapeptide hydrogen bonds along the stretching coordinate. As the decaalanine helix is stretched, the initially stabilized i → i + 4 contacts (α-helix) is replaced by i → i + 3 contacts (3(10)-helix). No significant formation of i → i + 5 hydrogen bonds (π-helix) is observed.

Neuropeptide Y (NPY) has been found to adopt two stable conformations in vivo: (1) a monomeric form called the PP-fold in which a polyproline tail is folded onto an α-helix via a β-turn and (2) a dimeric form of the unfolded proteins in which the α-helices interact with each other via side chains. The transition pathway and rates between the two conformations remain unknown and are important to the nature of the binding of the protein. Toward addressing this question, the present work suggests that the unfolding of the PP-fold is too slow to play a role in NPY monomeric binding unless the receptor catalyzes it to do so. Specifically, the dynamics and structural changes of the unfolding of a monomeric NPY protein have been investigated in this work. Temperature accelerated molecular dynamics (MD) simulations at 500 K under constant (N,V,E) conditions suggests a hinge-like unraveling of the tail rather than a random unfolding. The free energetics of the proposed unfolding pathway have been described using an adaptive steered MD (SMD) approach at various temperatures. This approach generalizes the use of Jarzynski's equality through a series of stages that allows for better convergence along nonlinear and long-distance pathways. Results acquired using this approach provide a potential of mean force (PMF) with narrower error bars and are consistent with some of the earlier reports on the qualitative behavior of NPY binding.

The nonequilibrium stretching of decaalanine in vacuum using steered molecular dynamics and Jarzynski's relation led to the landmark determination of its potential of mean force by Park and Schulten (Chem. Phys. 2004). In so doing, the relative thermodynamics of the hydrogen-bond contacts and the entropy of the chain were quantified through the reversible work, the potential of mean force (PMF). A recently developed adaptive steered molecular dynamics algorithm (Ozer et al. J. Chem. Theory Comput. 2010) has now made it possible to determine the thermodynamics, PMF, of the stretching of decaalanine in a model solvent of TIP3P water molecules. The loss of internal hydrogen bonds and the formation of hydrogen bonds between the peptide and the solvent has also been tracked with the corresponding stabilization in the PMF. As in the vacuum, most of the thermodynamic penalty to unravel the chain in solvent occurs during the regime when the internal hydrogen bonds are broken. The formation of hydrogen bonds with the solvent provides a significant stabilization not seen in vacuum, reducing the total energy cost to unravel by nearly a factor of 2.