@article {152899, title = {The alteration of structural network upon transient association between proteins studied using graph theory.}, journal = {Proteins}, volume = {93}, year = {2025}, month = {2025 Jan}, pages = {217-225}, abstract = {

Proteins such as enzymes perform their function by predominant non-covalent bond interactions between transiently interacting units. There is an impact on the overall structural topology of the protein, albeit transient nature of such interactions, that enable proteins to deactivate or activate. This aspect of the alteration of the structural topology is studied by employing protein structural networks, which are node-edge representative models of protein structure, reported as a robust tool for capturing interactions between residues. Several methods have been optimized to collect meaningful, functionally relevant information by studying alteration of structural networks. In this article, different methods of comparing protein structural networks are employed, along with spectral decomposition of graphs to study the subtle impact of protein-protein interactions. A detailed analysis of the structural network of interacting partners is performed across a dataset of around 900 pairs of bound complexes and corresponding unbound protein structures. The variation in network parameters at, around, and far away from the interface are analyzed. Finally, we present interesting case studies, where an allosteric mechanism of structural impact is understood from communication-path detection methods. The results of this analysis are beneficial in understanding protein stability, for future engineering, and docking studies.

}, keywords = {Algorithms, Allosteric Regulation, Databases, Protein, Models, Molecular, Protein Binding, Protein Conformation, Protein Interaction Mapping, Protein Interaction Maps, Proteins}, issn = {1097-0134}, doi = {10.1002/prot.26606}, author = {Prabantu, Vasam Manjveekar and Tandon, Himani and Sandhya, Sankaran and Sowdhamini, Ramanathan and Srinivasan, Narayanaswamy} } @article {144804, title = {Normal Mode Analysis Elicits Conformational Shifts in Proteins at Both Proximal and Distal Regions to the Phosphosite Stemming from Single-Site Phosphorylation.}, journal = {ACS Omega}, volume = {9}, year = {2024}, month = {2024 Jun 11}, pages = {24520-24537}, abstract = {

Phosphorylation, a fundamental biochemical switch, intricately regulates protein function and signaling pathways. Our study employs extensive computational structural analyses on a curated data set of phosphorylated and unphosphorylated protein pairs to explore the multifaceted impact of phosphorylation on protein conformation. Using normal mode analysis (NMA), we investigated changes in protein flexibility post-phosphorylation, highlighting an enhanced level of structural dynamism. Our findings reveal that phosphorylation induces not only local changes at the phosphorylation site but also extensive alterations in distant regions, showcasing its far-reaching influence on protein structure-dynamics. Through in-depth case studies on polyubiquitin B and glycogen synthase kinase-3 beta, we elucidate how phosphorylation at distinct sites leads to variable structural and dynamic modifications, potentially dictating functional outcomes. While phosphorylation largely preserves the residue motion correlation, it significantly disrupts low-frequency global modes, presenting a dualistic impact on protein dynamics. We also explored alterations in the total accessible surface area (ASA), emphasizing region-specific changes around phosphorylation sites. This study sheds light on phosphorylation-induced conformational changes, dynamic modulation, and surface accessibility alterations, leveraging an integrated computational approach with RMSD, NMA, and ASA, thereby contributing to a comprehensive understanding of cellular regulation and suggesting promising avenues for therapeutic interventions.

}, issn = {2470-1343}, doi = {10.1021/acsomega.4c00523}, author = {Subhadarshini, Seemadri and Tandon, Himani and Srinivasan, Narayanaswamy and Sowdhamini, Ramanathan} } @article {77391, title = {Mechanism of CcdA-Mediated Rejuvenation of DNA Gyrase.}, journal = {Structure}, volume = {28}, year = {2020}, month = {2020 May 05}, pages = {562-572.e4}, abstract = {

Most biological processes involve formation of transient complexes where binding of a ligand allosterically modulates function. The ccd toxin-antitoxin system is involved in plasmid maintenance and bacterial persistence. The CcdA antitoxin accelerates dissociation of CcdB from its complex with DNA gyrase, binds and neutralizes CcdB, but the\ mechanistic details are unclear. Using a series of experimental and\ computational approaches, we\ demonstrate the\ formation of transient ternary and quaternary CcdA:CcdB:gyrase complexes and\ delineate the molecular steps involved in the rejuvenation process. Binding of region 61-72 of CcdA to CcdB induces the vital structural and dynamic changes required to facilitate dissociation from gyrase, region 50-60 enhances the dissociation process through additional allosteric effects, and segment 37-49 prevents gyrase rebinding. This study provides insights into molecular mechanisms responsible for recovery of\ CcdB-poisoned cells from a persister-like state. Similar methodology can be used to characterize other important transient, macromolecular complexes.

}, issn = {1878-4186}, doi = {10.1016/j.str.2020.03.006}, author = {Aghera, Nilesh K and Prabha, Jyothi and Tandon, Himani and Chattopadhyay, Gopinath and Vishwanath, Sneha and Srinivasan, Narayanaswamy and Varadarajan, Raghavan} }