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 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.
An active infection-control intervention, which includes the obtaining of surveillance cultures and the isolation of infected patients, can reduce or eliminate the transmission of vancomycin-resistant enterococci in the health care facilities of a region.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.