Antiviral compounds modulate elasticity, strength and material fatigue of a virus capsid framework

Abstract

This study investigates whether the biochemical and antiviral effects of organic compounds that bind different sites in the mature human immunodeficiency virus capsid may be related to the modulation of different mechanical properties of the protein lattice from which the capsid is built. Mechanical force was used as a probe to quantify, in atomic force microscopy experiments at physiological pH and ionic strength, ligand-mediated changes in capsid lattice elasticity, breathing, strength against local dislocation by mechanical stress, and resistance to material fatigue. The results indicate that the effects of the tested compounds on assembly or biochemical stability can be linked, from a physics-based perspective, to their interference with the mechanical behavior of the viral capsid framework. The antivirals CAP-1 and CAI-55 increased the intrinsic elasticity and breathing of the capsid protein lattice and may entropically decrease the probability of the capsid protein to assemble into a functionally competent conformation. Antiviral PF74 increased the resistance of the capsid protein lattice to disruption by mechanical stress and material fatigue and may enthalpically strengthen the basal capsid lattice against breakage and disintegration. This study provides proof of concept that the interrogation of the mechanical properties of the nanostructured protein material that makes a virus capsid may provide fundamental insights into the biophysical action of capsid-binding antiviral agents. The implications for drug design by specifically targeting the biomechanics of viruses are discussed.