The SARS-CoV-2 RNA-dependent RNA polymerase drives viral genome replication and is a major antiviral target. How intrinsic conformational dynamics organize functional states of the polymerase, however, remains incompletely understood. Here, molecular dynamics (MD) simulations combined with free energy landscape analysis reveal that the apo polymerase samples preexisting conformational states defined by coordinated thumb-subdomain motions. Projection of experimental structures, representative of the polymerase nucleic acid cycle, onto the conformational landscape identified discrete basins spanning apo like and elongation-like states and revealed a coherent structural axis coupling global polymerase compaction (radius of gyration, Rg) with thumb interface separation (center-of-mass distance, COM). These motions connect catalytic motifs, RNA-binding regions, and distal regulatory elements across the polymerase ensemble. The observed conformational organization is not apparent from static structures alone and supports a model in which functional transitions arise from intrinsic collective dynamics of the apo enzyme. Intermediate conformational ensembles combine structural stability with retained inter-domain flexibility, identifying mechanically responsive states favorable for allosteric modulation. Together, these findings define structurally coupled regulatory regions within the coronavirus polymerase and support conformational trapping of thumb-subdomain dynamics as a potential strategy for antiviral design targeting RNA virus replication machinery.
Gibbs, H., Butuc, A., Moore, P. B., Gianti, E.
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