Energy Landscape Remodeling of Nucleic Acids by Multivalent Protein Binding

Abstract

Abstract The folding and assembly of nucleic acids are traditionally described in terms of intrinsic base pairing, stacking interactions, and topological constraints. However, in cellular environments, these energy landscapes are continuously reshaped by multivalent protein binding. In this chapter, we present a unified energy landscape framework in which protein-nucleic acid interactions are viewed not merely as binding events, but as active remodeling processes that reorganize the free energy surface of DNA and RNA substrates. Using transcription factors as model multivalent binders, we demonstrate how partially bound intermediates create metastable states that enable concentration-dependent facilitated dissociation and pathway switching. Rather than acting through simple collision-driven replacement, competing proteins reshape the population distribution across landscape minima, thereby altering nucleic acid occupancy lifetimes and exchange kinetics. When multiple proteins assemble on the same nucleic acid, cooperative configurations emerge that introduce new dissociation channels and stoichiometry-sensitive switches, effectively redefining the topology of the underlying energy surface and enabling systems biology-level control of gene expression through tunable multibody interactions. Beyond protein multiplicity, we show that nucleic acid mechanical properties—particularly sequence-dependent elasticity—couple electrostatics, conformational entropy, and bending rigidity to produce indirect readout mechanisms. In this view, specificity arises from protein-induced modulation of nucleic acid flexibility rather than solely from direct base recognition. Intersegment transfer further expands this landscape perspective, as multibody, orientation-constrained intermediates allow proteins to bridge distinct nucleic acid segments, coupling binding dynamics to topological states such as supercoiling and torsional stress. Together, these results position multivalent protein binding as a central mechanism for remodeling nucleic acid energy landscapes across multiple scales—from local conformational states to chromosome-level organization. This perspective extends classical folding and assembly theories toward a dynamic, architecture-aware framework for understanding nucleic acid behavior in living systems.