UC San Diego

An extended accelerated molecular dynamics (AMD) methodology called adaptive AMD is presented. Adaptive AMD (Ad-AMD) is an efficient and robust conformational space sampling algorithm that is particularly-well suited to proteins with highly structured potential energy surfaces exhibiting complex, large-scale collective conformational transitions. Ad-AMD simulations of substrate-free P450cam reveal that this system exists in equilibrium between a fully and partially open conformational state. The mechanism for substrate binding depends on the size of the ligand. Larger ligands enter the P450cam binding pocket, and the resulting substrate-bound system is trapped in an open conformation via a population shift mechanism. Small ligands, which fully enter the binding pocket, cause an induced-fit mechanism, resulting in the formation of an energetically stable closed conformational state. These results are corroborated by recent experimental studies and potentially provide detailed insight into the functional dynamics and conformational behavior of the entire cytochrome-P450 superfamily.