%0 Journal Article %A Lei Dai %A Yushen Du %A Hangfei Qi %A Nicholas C. Wu %A Ergang Wang %A James O. Lloyd-Smith %A Ren Sun %T Adaptive potential of a drug-targeted viral protein as a function of positive selection %D 2017 %R 10.1101/078428 %J bioRxiv %P 078428 %X RNA viruses are notorious for their ability to evolve rapidly under positive selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes. Here we systematically quantified the distribution of fitness effects (DFE) of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of Hepatitis C Virus (HCV). We found that the majority of non-synonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized in natural conditions. We characterized the adaptive potential of HCV by subjecting the mutant viruses to positive selection by the NS5A inhibitor Daclatasvir. Both the selection coefficient and the number of beneficial mutations are found to increase with the strength of positive selection, which is modulated by the concentration of Daclatasvir. The shift in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. Finally, our large-scale fitness data of mutant viruses also provide insights into the biophysical basis of evolutionary constraints in protein evolution. %U https://www.biorxiv.org/content/biorxiv/early/2017/08/04/078428.full.pdf