Structure and dynamics of the GH loop of the foot-and-mouth disease virus capsid

Area of Science:

• Virology
• Structural Biology
• Biophysics

Background:

• The GH loop of foot-and-mouth disease virus (FMDV) VP1 is a key antigenic site and mediates integrin binding.
• This loop is typically disordered in X-ray structures, except in reduced serotype O capsids where it lies on the surface.
• Previous studies suggest the GH loop protrudes upon binding to antigen-binding fragments (Fab).

Purpose of the Study:

• To elucidate the structure and dynamics of the FMDV serotype O GH loop under natural, unreduced conditions prior to integrin or Fab binding.
• To investigate the conformational changes induced by disulfide bond formation at the GH loop base.

Main Methods:

• 16.3 ns molecular dynamics (MD) simulation of the FMDV serotype O capsid.
• Rotational symmetry boundary conditions were applied.
• Initial coordinates were derived from the X-ray structure of the reduced capsid, with a molecular mutation method to form the disulfide bond.

Main Results:

• Formation of the disulfide bond caused the GH loop to protrude into surrounding water, exhibiting tentacle-like fluctuations.
• After equilibration, the GH loop fluctuated while oriented towards a 2-fold axis, partially overlapping the capsid surface.
• The conformational changes were modeled using an elastic tube model.
• Integrin recognition residues (RGD tripeptide) showed extended side chains, with C-terminal residues forming a hydrophobic cluster near arginine.

Conclusions:

• The disulfide bond is critical for the GH loop's dynamic protrusion and tentacle-like behavior.
• The study provides insights into the GH loop's conformational flexibility and interactions relevant to FMDV infection mechanisms.
• The findings contribute to understanding FMDV-host interactions at a molecular level.