title: Free energy and hidden barriers of the β-sheet structure of prion protein.
abstract: On-the-fly free-energy parametrization is a new collective variable biasing approach akin to metadynamics with one important distinction: rather than acquiring an accelerated distribution via a history-dependent bias potential, sampling on this distribution is achieved from the beginning of the simulation using temperature-accelerated molecular dynamics. In the present work, we compare the performance of both approaches to compute the free-energy profile along a scalar collective variable measuring the H-bond registry of the β-sheet structure of the mouse Prion protein. Both methods agree on the location of the free-energy minimum, but free-energy profiles from well-tempered metadynamics are subject to a much higher degree of statistical noise due to hidden barriers. The sensitivity of metadynamics to hidden barriers is shown to be a consequence of the history dependence of the bias potential, and we detail the nature of these barriers for the prion β-sheet. In contrast, on-the-fly parametrization is much less sensitive to these barriers and thus displays improved convergence behavior relative to that of metadynamics. While hidden barriers are a frequent and central issue in free-energy methods, on-the-fly free-energy parametrization appears to be a robust and preferable method to confront this issue.
authors.affiliation: Department of Chemical and Biological Engineering, Drexel University , Philadelphia, Pennsylvania 19104, United States.
authors.forename: S Alexis
authors.initials: SA
authors.lastname: Paz
authors.affiliation: Department of Chemical and Biological Engineering, Drexel University , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Cameron F
authors.initials: CF
authors.lastname: Abrams
mesh_terms: D000818:Animals; D006860:Hydrogen Bonding; D051379:Mice; D056004:Molecular Dynamics Simulation; D011328:Prions / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D011328:Prions