An all-atom view into the disordered interaction interface of the TRIM5α PRYSPRY domain and the HIV capsid

Tripartite motif-containing protein 5, alpha isoform (TRIM5) is an innate immune factor that provides rhesus macaques with immunity to HIV. Despite high sequence similarity to rhesus TRIM5, human TRIM5 does not restrict HIV without the introduction of mutations. The structural underpinnings of this functional difference are poorly understood because the interaction interface between the HIV capsid and TRIM5 involves intrinsically disordered regions. Here, we use all-atom molecular dynamics simulations to study several TRIM5 variants: rhesus TRIM5, human TRIM5, and human TRIM5 with the R332P mutation (a mutation known to enhance HIV restriction). Our data reveal differences in the conformational ensembles of wild-type and R332P human TRIM5, including a significant increase in the formation of a turn that includes the mutation site residue. We also carried out simulations of rhesus TRIM5 in complex with the HIV capsid protein. Our results indicate that the variable loops of TRIM5 are highly flexible, both in solution and in the complex with the capsid protein, indicative of a fuzzy interaction interface. Simulations of the complex suggest a plausible mechanism for HIV restriction by TRIM5 with the R332P mutation; replacing the positively charged arginine with a neutral residue enhances electrostatic interactions with residue R82 of the capsid protein. Overall, our simulations provide a first view of the atomistic details of the HIV capsid-TRIM5 binding interface, providing a potential molecular mechanism for the observed functional differences between variants of the TRIM5 protein.