MACV

MACV analyzes interactions between the Machupo virus spike glycoprotein (GP1) and the human transferrin receptor (hTfR1) using steered molecular dynamics to assess binding affinity and mutational effects on the protein-protein interface.

Key Features:

• Steered Molecular Dynamics (SMD) Simulations: Performs SMD to pull GP1 away from hTfR1 and records force profiles, including maximum applied force and the area under the force-versus-distance curve.
• Affinity Estimation without Free Energy Calculations: Approximates relative binding affinity from SMD-derived metrics rather than performing rigorous free energy calculations.
• Correlation with Free Energy Perturbation (FEP): Compares SMD-derived quantities with relative free energy differences obtained via free energy perturbation to validate predictive power.
• Dynamic Interface and Hydrogen-Bonding Analysis: Interprets SMD trajectories to evaluate the functional importance of hydrogen-bonding networks at the GP1/hTfR1 interface, including identification of networks that may be nonessential for tight binding despite co-crystal evidence.
• Mutational Effect Analysis: Evaluates individual and multiple mutations, including non-alanine substitutions and modifications in flexible loops, to identify critical viral sites and potential evolutionary suppressor sites affecting infection-resistant receptor mutants.

Scientific Applications:

• Virology and Host Interaction Studies: Provides computational insights into how mutations in GP1 or hTfR1 affect viral binding and entry into human cells.
• Drug Design and Therapeutic Development: Identifies critical interaction sites at the GP1/hTfR1 interface that can inform antiviral targeting strategies.
• Evolutionary Biology: Highlights suppressor sites and mutational effects that inform studies of viral adaptation to host resistance mechanisms.

Methodology:

Set up steered molecular dynamics simulations that pull GP1 away from hTfR1, record force-vs-distance data, compute maximum applied force and area under the force-versus-distance curve, and analyze these SMD-derived metrics to approximate relative binding affinity and compare with free energy perturbation results.