Hierarchical Conformational Analysis of Native Lysozyme Based on Sub-Millisecond Molecular Dynamics Simulations

Area of Science:

• Biophysics
• Computational Biology
• Protein Dynamics

Background:

• The hierarchical organization of protein free energy landscapes (FEL) is widely accepted.
• FELs are typically analyzed in low dimensions, potentially oversimplifying complex dynamics.
• Understanding protein conformational substates is crucial for molecular function.

Purpose of the Study:

• To investigate the conformational dynamics of hen egg white lysozyme (HEWL) using extensive molecular dynamics simulations.
• To analyze the topology of HEWL's FEL at various temporal resolutions.
• To characterize the nature of conformational substates and transition states.

Main Methods:

• Generated 0.2 millisecond molecular dynamics simulation trajectories for HEWL in explicit solvent.
• Performed detailed conformational analysis using backbone torsional degrees of freedom.
• Examined FEL topology at microsecond and nanosecond temporal resolutions.

Main Results:

• At microsecond resolution, HEWL's FEL shows a hub-like topology with crystal structures as the dominant ensemble.
• At nanosecond resolution, the FEL exhibits a network-like topology, with crystal structures as kinetic traps.
• Transition state ensembles are disordered and their lifetimes are largely independent of torsional degrees of freedom timescales.

Conclusions:

• The topology of protein FELs is resolution-dependent, transitioning from hub-like to network-like at finer timescales.
• Detailed analysis of conformational substates across multiple temporal resolutions is both important and feasible.
• The findings provide a more nuanced understanding of protein conformational flexibility and dynamics.