Free energy and hidden barriers of the beta-sheet structure of the Prion protein

PAZ SERGIO ALEXIS; CAMERON F. ABRAMS

JOURNAL OF CHEMICAL THEORY AND COMPUTATION

AMER CHEMICAL SOC

Lugar: Washington; Año: 2015

1549-9618

n-the-fly free-energy parameterization 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 $eta$-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 $eta$-sheet. In contrast, on-t