Dynamic insights into the structural evolution of ACE2-RBD interactions through molecular dynamics simulation, Markov...

Area of Science:

• Molecular biology
• Structural biology
• Computational virology

Background:

• The SARS-CoV-2 Spike protein's receptor-binding domain (RBD) mediates host cell entry by binding to angiotensin-converting enzyme 2 (ACE2).
• Existing structural studies lack dynamic insights into ACE2-RBD interactions, particularly for emerging variants.
• Conventional analysis of molecular dynamics (MD) simulations often fails to adequately detect and analyze metastable states.

Purpose of the Study:

• To analyze the dynamic and thermodynamic properties of the ACE2-RBD complex for SARS-CoV-2 wild type and Omicron variants (BA.2, BA.2.86, JN.1).
• To establish a robust method for extracting detailed kinetic and thermodynamic insights from extensive MD simulations.
• To provide a dynamic, atomic-level understanding of ACE2-RBD interactions and their evolution.

Main Methods:

• Extensive molecular dynamics (MD) simulations of ACE2-RBD complexes.
• Time-lagged independent component analysis-Markov State Models (TICA-MSM) for analyzing metastable states.
• Scanning point mutations on RBD, evaluation with a large language model, and analysis of structural interactions.

Main Results:

• Identification of four principal metastable states for each ACE2-RBD system studied.
• Demonstration that lineage-defining mutations systematically alter thermodynamic properties (equilibrium populations, interaction energies) and transition kinetics.
• Detailed, dynamic, atomic-level view of structural evolution at the ACE2-RBD binding interface.

Conclusions:

• The TICA-MSM approach offers a superior paradigm for analyzing MD simulation data, revealing critical dynamic and thermodynamic insights.
• Lineage-defining mutations significantly impact the ACE2-RBD interaction landscape, influencing viral behavior.
• This research provides a mechanistic basis for enhanced viral surveillance and the design of targeted therapeutics against SARS-CoV-2 variants.