Abstract
Hierarchical organization of free energy landscape (FEL) for native globular proteins has been widely accepted by the biophysics community. However, FEL of native proteins is usually projected onto one or a few dimensions. Here we generated collectively 0.2 milli-second molecular dynamics simulation trajectories in explicit solvent for hen egg white lysozyme (HEWL), and carried out detailed conformational analysis based on backbone torsional degrees of freedom (DOF). Our results demonstrated that at micro-second and coarser temporal resolutions, FEL of HEWL exhibits hub-like topology with crystal structures occupying the dominant structural ensemble that serves as the hub of conformational transitions. However, at 100ns and finer temporal resolutions, conformational substates of HEWL exhibit network-like topology, crystal structures are associated with kinetic traps that are important but not dominant ensembles. Backbone torsional state transitions on time scales ranging from nanoseconds to beyond microseconds were found to be associated with various types of molecular interactions. Even at nanoseconds temporal resolution, the number of conformational substates that are of statistical significance is quite limited. These observations suggest that detailed analysis of conformational substates at multiple temporal resolutions is both important and feasible. Transition state ensembles among various conformational substates at microsecond temporal resolution were observed to be considerably disordered. Life times of these transition state ensembles are found to be nearly independent of the time scales of the participating torsional DOFs.
Highlights
During last two decades, great progress has been made in the study of major conformational transitions for some functionally important proteins [1,2,3,4,5,6,7,8,9,10]
127 backbone dihedrals with two-major-peak distributions were defined as two-state torsional degrees of freedom (DOF), and were divided into 5 different temporal resolutions according to the number of observed transitions between the two torsional state of each selected torsion
Various molecular interactions captured in crystal structural ensemble (CSE) were found to associate with conformational substates (CSs) transitions covering time scales from nanoseconds to microseconds
Summary
Great progress has been made in the study of major conformational transitions for some functionally important proteins [1,2,3,4,5,6,7,8,9,10].
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