Protein dynamics investigated by inherent structure analysis

Molecular dynamics (MD) simulations provide essential information about the thermodynamics and dynamics of proteins. To construct the free-energy surface from equilibrium trajectories, it is necessary to group the individual snapshots in a meaningful way. The inherent structures (IS) are shown to provide an appropriate discretization of the trajectory and to avoid problems that can arise in clustering algorithms that have been employed previously. The IS-based approach is illustrated with a 30-ns room temperature "native" state MD simulation of a 10-residue peptide in a beta-hairpin conformation. The transitions between the IS are used to construct a configuration space network from which a one-dimensional free-energy profile is obtained with the mincut method. The results demonstrate that the IS approach is useful and that even for this simple system, there exists a nontrivial organization of the native state into several valleys separated by barriers as high as 3 kcal/mol. Further, by introducing a coarse-grained network, it is demonstrated that there are multiple pathways connecting the valleys. This scenario is hidden when the snapshots of the trajectory are used directly with rmsd clustering to compute the free-energy profile. Application of the IS approach to the native state of the PDZ2 signaling domain indicates its utility for the study of biologically relevant systems.