The energy landscape reshaped by strain-specific mutations underlies the long-range epistasis in NS1 evolution of influenza A virus

Abstract

The mechanisms underlying how individual mutations affect the protein energy landscape are crucial for understanding how proteins evolve. However, predicting mutational effects remains challenging because of epistasis—the nonadditive interactions between mutations. Here, we investigate the biophysical mechanism of strain-specific epistasis in the nonstructural protein 1 (NS1) of the influenza A virus (IAV). To understand the molecular basis of epistasis, we conducted comprehensive analyses of four NS1s of IAV strains that emerged between 1918 and 2004. We find that strain-specific mutations of NS1s are near-neutral with respect to the association with the p85β subunit of PI3K. However, the individual residues on the p85β-binding interface show long-range epistatic interactions with strain-specific mutations. We reveal that strain-specific mutations reshaped the energy landscape of NS1, leading to long-range epistasis. Our findings offer a high-resolution mechanism of how near-neutral mutations silently alter the biophysical energy landscapes, resulting in diverse background effects during molecular evolution.

Markov State Models and Perturbation-Based Approaches Reveal Distinct Dynamic Signatures and Hidden Allosteric Pockets in the Emerging SARS-Cov-2 Spike Omicron Variants Complexes with the Host Receptor: The Interplay of Dynamics and Convergent Evolution Modulates Allostery and Functional Mechanisms

“…Patterns of convergence are often offered as compelling evidence of adaptation and recent studies indicated that allosteric interactions in proteins not only dictate long-range couplings and signal transmission patterns but are also essential in the evolutionary adaptation of proteins. 134,135 It has been recognized that allosteric mechanisms regulate emergence and contribution of different conformational states and shape up functional landscapes, enabling evolutionary adaptation of new functions through controlled modulation of conformational plasticity. 135 We hypothesized that sites of convergent mutations target specific structural hotspot of adaptation that may be organized through engagement to the pre-existing allosteric network.…”

“…134,135 It has been recognized that allosteric mechanisms regulate emergence and contribution of different conformational states and shape up functional landscapes, enabling evolutionary adaptation of new functions through controlled modulation of conformational plasticity. 135 We hypothesized that sites of convergent mutations target specific structural hotspot of adaptation that may be organized through engagement to the pre-existing allosteric network.…”