{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:02:08Z","timestamp":1785402128919,"version":"3.56.0"},"posted":{"date-parts":[[2025,11,12]]},"group-title":"Biophysics","reference-count":95,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01AI169896"],"award-info":[{"award-number":["R01AI169896"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Science Foundation","award":["OAC-1818253"],"award-info":[{"award-number":["OAC-1818253"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates viral entry by binding its receptor-binding domain (RBD) to the host receptor ACE2. Spike mutations in different variants have been experimentally shown to influence the rate of conformational transitions and alter viral infectivity. In parallel, both experimental and computational studies have reported the presence of long-range allosteric communication within the spike protein, suggesting that such mutations may also affect allosteric signaling pathways involved in viral function. A detailed understanding of the allosteric residue network is essential for rational antiviral drug design. In this study, we performed extensive atomistic molecular dynamics (MD) simulations of the spike proteins from the Delta and Omicron variants in both ACE2-bound and unbound states. By integrating linear mutual information (LMI) calculations and graph theory-based analysis, we delineated the long-range allosteric communication networks embedded within the spike protein. Betweenness centrality metrics enabled the identification of residues that act as key mediators of information flow. Notably, ACE2 binding markedly enhances allosteric coupling throughout the spike. We identified three key linkers, Link1 (NTD-RBD), Link2 (RBD-SD1), and Link3 (SD2-FP), as primary mediators of allosteric communication. Delta exhibits stronger signaling through Link1 and Link2, whereas Omicron redirects communication via Link3. While Delta maintains localized connectivity within the S1 domain but loses long-range contact with the S2 core, Omicron forms a broader yet weaker S1 network and establishes long-range coupling. We propose that the N856K and T547K mutations reshape the conformational landscape, reconfiguring allosteric communication pathways in Omicron. Furthermore, our analysis reveals distinct domain-level allosteric couplings in Delta and Omicron, pointing to variant-specific differences in fusogenicity and immune evasion. By mapping key allosteric sites and mutation-induced conformational shifts, our study may provide a framework for developing robust antiviral strategies resilient to future emerging SARS-CoV-2 variants.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>Receptor engagement at the RBD rewires long range allostery in the SARS CoV 2 spike. Using LMI and graph theory-based analyses, we map communication paths and pinpoint residues that govern spike opening and infection. ACE2 binding globally strengthens coupling, but energy and signals propagate along variant specific routes: Delta biases toward openness, channeling binding energy into RBD opening; Omicron remains less open, routing energy to the S2 core to prime fusion. Information flows through three linkers - Link1 (NTD to RBD), Link2 (RBD to SD1), and Link3 (SD2 to FP), with Delta emphasizing Link1\/Link2 and Omicron shifting to Link3 and CD connections. We suggest that the N856K and T547K mutations reshape this landscape in Omicron.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.12.688084","type":"posted-content","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T03:00:13Z","timestamp":1763002813000},"source":"Crossref","is-referenced-by-count":0,"title":["Mutation and ACE2-induced Allosteric Network Rewiring in Delta and Omicron SARS-CoV-2 Spike Proteins"],"prefix":"10.64898","author":[{"given":"Mandira","family":"Dutta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Voth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111409300716000_2025.11.12.688084v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(65)80285-6"},{"issue":"3","key":"2025111409300716000_2025.11.12.688084v1.2","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/prot.20232","article-title":"Is allostery an intrinsic property of all dynamic proteins?","volume":"57","year":"2004","journal-title":"Proteins: Structure, Function, and Bioinformatics"},{"issue":"26","key":"2025111409300716000_2025.11.12.688084v1.3","doi-asserted-by":"crossref","first-page":"21921","DOI":"10.1021\/acsomega.9b02946","article-title":"Role of AAA3 Domain in Allosteric Communication of Dynein Motor Proteins","volume":"4","year":"2019","journal-title":"ACS Omega"},{"key":"2025111409300716000_2025.11.12.688084v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.02.034"},{"key":"2025111409300716000_2025.11.12.688084v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023659118"},{"key":"2025111409300716000_2025.11.12.688084v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2090"},{"key":"2025111409300716000_2025.11.12.688084v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.28212"},{"key":"2025111409300716000_2025.11.12.688084v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00418-x"},{"key":"2025111409300716000_2025.11.12.688084v1.9","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.75433"},{"key":"2025111409300716000_2025.11.12.688084v1.10","doi-asserted-by":"crossref","unstructured":"Barton, M. 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