Hexagonal Lattices of HIV Capsid Proteins Explored by Simulations Based on a Thermodynamically Consistent Model

Area of Science:

• Structural biology
• Biophysics
• Computational modeling

Background:

• HIV capsid proteins (CAs) self-assemble into diverse structures in vitro and in vivo.
• Understanding the mechanisms of CA assembly is crucial for HIV research.

Purpose of the Study:

• To investigate the self-assembly of HIV capsid proteins into hexagonal lattices using simulations.
• To model the spontaneous curvature and aggregation dynamics of CA structures.

Main Methods:

• Utilized a residue-level coarse-grained (CG) model with full conformational flexibility.
• Employed enhanced sampling simulations to calculate CA dimerization and polymerization affinities.
• Performed unbiased simulations on large systems (1512 CA subunits) with reversible binding.

Main Results:

• Simulations reproduced experimentally measured CA binding affinities.
• Observed spontaneous curvature development in hexagonal CA sheets, with larger local curvatures at edges.
• Demonstrated CA assembly growth via capsomere binding and merging of aggregates.
• At high concentrations, initial aggregation was followed by slower formation of regular hexagonal lattices.

Conclusions:

• The study provides a practical strategy for simulating protein aggregations by calibrating CG models with experimental data.
• The findings elucidate the mechanisms underlying HIV capsid protein assembly and structural variations.