Biophysical determinants of mutational robustness in a viral molecular fitness landscape
Abstract
Biophysical interactions between proteins and peptides are key determinants of genotype-fitness landscapes, but an understanding of how molecular structure and residue-level energetics at protein-peptide interfaces shape functional landscapes remains elusive. Combining information from yeast-based library screening, next-generation sequencing and structure-based modeling, we report comprehensive sequence-energetics-function mapping of the specificity landscape of the Hepatitis C Virus (HCV) NS3/4A protease, whose function — site-specific cleavages of the viral polyprotein — is a key determinant of viral fitness. We elucidate the cleavability of 3.2 million substrate variants by the HCV protease and find extensive clustering of cleavable and uncleavable motifs in sequence space indicating mutational robustness, and thereby providing a plausible molecular mechanism to buffer the effects of low replicative fidelity of this RNA virus. Specificity landscapes of known drug-resistant variants are similarly clustered. Our results highlight the key and constraining role of molecular-level energetics in shaping plateau-like fitness landscapes from quasispecies theory.
Related Papers
- → Hepatitis C Virus Population Dynamics During Infection(2006)109 cited
- → Quasispecies on Fitness Landscapes(2015)48 cited
- → Trends for genetic variation of Hepatitis C Virus quasispecies in Human Immunodeficiency virus-1 coinfected patients(2007)16 cited
- → Adaptation dynamics of the quasispecies model(2008)
- → NS3 genetic variability in HCV genotype 1a isolates from liver tissues and serum samples of treatment-naïve patients with chronic hepatitis C(2016)