Sampling activated mechanisms in proteins with the activation-relaxation technique

The activated dynamics of proteins occur on rime scales of milliseconds and longer Standard all-atom molecular dynamics simulations are limited to much shorter times, of the order of tens of nanoseconds. Therefore, many activated mechanisms that are crucial for long-time dynamics will nor be observed in such molecular dynamics simulation; different methods are required Here, roe describe in derail the activation-relaxation technique (ART) that generates directly activated mechanisms. The method is defined in the configurational energy landscape and defines moves in a two step fashion: (a) a configuration is first sr bi-ought from a local minimum to a nearby first-order saddle point (the activation); and (b) the configuration is relaxed to a new metastable state (the relaxation). The method has already been applied to a wide range of problems in condensed matter, including metallic glasses, amorphous semiconductors and silica glass. We review the algorithm in detail, discuss some previously published results and present simulations of activated mechanisms for a two-helix bundle protein using an all-atom energy function. (C) 2001 by Elsevier Science Inc.