Density guided importance sampling: application to a reduced model of protein folding

MOTIVATION: Monte Carlo methods are the most effective means of exploring the energy landscapes of protein folding. The rugged topography of folding energy landscapes causes sampling inefficiencies however, particularly at low, physiological temperatures. RESULTS: A hybrid Monte Carlo method, termed density guided importance sampling (DGIS), is presented that overcomes these sampling inefficiencies. The method is shown to be highly accurate and efficient in determining Boltzmann weighted structural metrics of a discrete off-lattice protein model. In comparison to the Metropolis Monte Carlo method, and the hybrid Monte Carlo methods, jump-walking, smart-walking and replica-exchange, the DGIS method is shown to be more efficient, requiring no parameter optimization. The method guides the simulation towards under-sampled regions of the energy spectrum and recognizes when equilibrium has been reached, avoiding arbitrary and excessively long simulation times. AVAILABILITY: Fortran code available from authors upon request. CONTACT: m.j.parker@leeds.ac.uk.