Biology subjects

Modi, T.

Publications and source records attributed to Modi, T..

3 recordsLinked to original sources

bioRxiv2023

Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of the S protein compared to the closed form. In particular, the CAP sites control the dynamics of binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly additive mutations. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding.

biophysics↗

bioRxiv2023

RNA-induced allosteric coupling drives viral capsid assembly in bacteriophage MS2

Understanding the mechanisms by which single-stranded RNA viruses regulate capsid assembly around their RNA genomes has become increasingly important for the development of both antiviral treatments and drug delivery systems. Here, we investigate the effects of RNA-induced allostery in a single-stranded RNA virus -- Levivirus bacteriophage MS2 -- using the computational methods of the Dynamic Flexibility Index (DFI) and the Dynamic Coupling Index (DCI). We show that asymmetric binding of RNA to a symmetric MS2 coat protein dimer increases the flexibility of the distant FG-loop and induces a conformational change to an asymmetric dimer that is essential for proper capsid formation. We also show that a point mutation W82R in the FG-loop creates an assembly-deficient dimer in which RNA-binding has no significant effect on FG-loop flexibility. Lastly, we show that the highly flexible disordered FG-loop of the RNA bound asymmetric dimer not only becomes the controller of the rigid FG-loop but enhances its dynamic coupling with all the distal positions in the dimer. This strong dynamic coupling allows highly regulated communication and unidirectional signal transduction that drives the formation of the experimentally observed capsid intermediates. Author summaryThe final stage of an RNA virus life cycle is the assembly of a protein shell encapsulating the viral genome prior to release from the host organism. Despite rapid advancements in both experimental and theoretical biology since the mid-20th century, little is still known about the underlying mechanisms of viral capsid assembly. However, understanding the biophysical principles of viral capsid assembly would bring us one step closer to developing new biotechnologies such as antivirals that inhibit this critical stage of the life cycle or artificial capsids for targeted drug/vaccine delivery. Although we limit the present study to one simple RNA virus that infects bacteria, we propose that the physical implications can extend to other RNA viruses including the human coronavirus SARS-CoV-2. We also propose that the allosteric regulation by specific protein-RNA interactions might be a general mechanism exploited by many other ribonucleoprotein complexes, such as CRISPR-Cas9, spliceosome or ribosome.

biophysics↗

bioRxiv2018

Ancient Thioredoxins Evolved to Modern Day Stability-Function Requirement by Altering Native State Ensemble

Thioredoxins (Thrxs) - small globular proteins that reduce other proteins - are ubiquitous in all forms of life, from archaea to mammals. Although ancestral Thioredoxins share sequential and structural similarity with the modern day (extant) homologs, they exhibit significantly different functional activity and stability. We investigate this puzzle by comparative studies of their (ancient and modern day Thrxs) native state ensemble, as quantified by the Dynamic Flexibility Index (DFI), a metric for the relative resilience of an amino acid to perturbations in the rest of the protein. Clustering proteins using DFI profiles strongly resembles an alternate classification scheme based on their activity and stability. The DFI profiles of the extant proteins are substantially different around the 3, 4 helices and catalytic regions. Likewise, allosteric coupling of the active site with the rest of the protein is different between ancient and extant Thrxs, possibly explaining the decreased catalytic activity at low pH with evolution. At a global level, we note that the population of low flexibility (called hinges) and high flexibility sites increases with evolution. The heterogeneity (quantified by the variance) in DFI distribution increases with the decrease in the melting temperature typically associated with the evolution of ancient proteins to their modern-day counterparts.

biophysics↗