arXiv subjects

Moitrayee Bhattacharyya

Publications and source records attributed to Moitrayee Bhattacharyya.

4 recordsLinked to original sources

arXiv2026

From atomic to global connectivity in the structure of the SARS-CoV2-Human ACE2 receptor complex

We investigate connectivity properties of the SARS-CoV2 spike protein-human ACE2-receptor complex employing a protein side chain-based network method that allows us to span a range from atomic to global protein scales. We analyze network topology in terms of clusters and cliques obtained from averaging over snapshots of MD simulations (from D.E. Shaw Research). We demonstrate that SARS-CoV2 forms a more dominant, robust connection with the ACE2-receptor as compared to the less virulent SARS-CoV1. Globally, this stronger connectivity is reflected by our percolation analysis where the interface cluster for the SARS-CoV2-ACE2 complex persists when restricted to stronger and stronger bonds, as compared to the SARSCoV1- ACE2 complex. At the atomic level, interface clique structure reflects a stronger connectivity in the former complex. We pinpoint key functional residues in SARSCoV2 that play important roles in establishing this higher connectivity. Thus, our studies provide an objective method to map spatial connectivity of atomic level non-covalent interactions to global connectivity between any two amino acids in the complex. We also analyze specific snapshots of the MD simulations to highlight prominent variations in network topology that explore diverse conformational landscapes. Finally, we demonstrate that a majority of mutations that occur in the SARSCoV2 spike protein in variants of concern/interest (including the currently circulating JN.1) have been observed at the interface with the ACE2 receptor. Our analyses highlight the importance of interface interactions and provide a rationale for designing receptor-like peptides and proteins to combat immunity-escaping variants.

physics.bio-ph↗

arXiv2020

Surveying the side-chain network approach to protein structure and dynamics: The SARS-CoV-2 spike protein as an illustrative case

Network theory-based approaches provide valuable insights into the variations in global structural connectivity between differing dynamical states of proteins. Our objective is to review network-based analyses to elucidate such variations, especially in the context of subtle conformational changes. We present technical details of the construction and analyses of protein structure networks, encompassing both the non-covalent connectivity and dynamics. We examine the selection of optimal criteria for connectivity based on the physical concept of percolation. We highlight the advantages of using side-chain based network metrics in contrast to backbone measurements. As an illustrative example, we apply the described network approach to investigate the global conformational change between the closed and partially open states of the SARS-CoV-2 spike protein. This conformational change in the spike protein is crucial for coronavirus entry and fusion into human cells. Our analysis reveals global structural reorientations between the two states of the spike protein despite small changes between the two states at the backbone level. We also observe some differences at strategic locations in the structures, correlating with their functions, asserting the advantages of the side-chain network analysis. Finally we present a view of allostery as a subtle synergistic-global change between the ligand and the receptor, the incorporation of which would enhance the drug design strategies.

q-bio.BM↗

arXiv2013

Activation-triggered subunit exchange between CaMKII holoenzymes facilitates the spread of kinase activity

The activation of the dodecameric Ca2+/calmodulin dependent kinase II (CaMKII) holoenzyme is critical for the formation of memory. We now report that CaMKII has a remarkable property, which is that activation of the holoenzyme triggers the exchange of subunits with other holoenzymes, including unactivated ones, enabling the calcium-independent phosphorylation and activation of new subunits. We show, using a single-molecule TIRF microscopy technique, that the exchange process is triggered by the activation of CaMKII, with the exchange rate being modulated by phosphorylation of two residues in the calmodulin-binding segment, Thr 305 and Thr 306. Based on these results, and on the analysis of molecular dynamics simulations, we suggest that the phosphorylated regulatory segment of CaMKII interacts with the central hub of the holoenzyme and weakens its integrity, thereby promoting exchange. Our results have implications for an earlier idea that subunit exchange in CaMKII may have relevance for the storage of information resulting from brief coincident stimuli during neuronal signaling.

q-bio.BM↗

arXiv2013

The dynamics and flexibility of protein disulphide-isomerase (PDI): predictions of experimentally-observed domain motions

We have studied the mobility of the folding catalyst, protein disulphide-isomerase (PDI), by molecular dynamics and by a rapid approach based on flexibility. We analysed our simulations using measures of backbone movement, relative positions and orientations of domains, and distances between functional sites. Despite their different assumptions, the two methods are surprisingly consistent. Both methods agree that motion of domains is dominated by hinge and rotation motion of the a and a' domains relative to the central b-b' domain core. We identify the a' domain as showing the greatest intra-domain mobility. The flexibility method, which requires 10^4-fold less computer power, predicts additional large-scale features of inter-domain motion that have been observed experimentally. We conclude that the methods offer complementary insight into the motion of this large protein and provide detailed structural models that characterise its functionally-significant conformational changes.

q-bio.BM↗