RNA's Dynamic Conformational Selection and Entropic Allosteric Mechanism in Controlling Cascade Protein Binding Events

J Phys Chem Lett. 2024 Jun 13;15(23):6115-6125. doi: 10.1021/acs.jpclett.4c00740. Epub 2024 Jun 3.

Abstract

In the TAR RNA of immunodeficiency viruses, an allosteric communication exists between a distant loop and a bulge. The bulge interacts with the TAT protein vital for transactivating viral RNA, while the loop interacts with cyclin-T1, contingent on TAT binding. Through extensive atomistic and free energy simulations, we investigate TAR-TAT binding in nonpathogenic bovine immunodeficiency virus (BIV) and pathogenic human immunodeficiency virus (HIV). Thermodynamic analysis reveals enthalpically driven binding in BIV and entropically favored binding in HIV. The broader global basin in HIV is attributed to binding-induced loop fluctuation, corroborated by nuclear magnetic resonance (NMR), indicating classical entropic allostery onset. While this loop fluctuation affects the TAT binding affinity, it generates a binding-competent conformation that aids subsequent effector (cyclin-T1) binding. This study underscores how two structurally similar apo-RNA scaffolds adopt distinct conformational selection mechanisms to drive enthalpic and entropic allostery, influencing protein affinity in the signaling cascade.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Cattle
  • Entropy*
  • Humans
  • Molecular Dynamics Simulation
  • Nucleic Acid Conformation*
  • Protein Binding*
  • RNA, Viral / chemistry
  • RNA, Viral / metabolism
  • Thermodynamics
  • tat Gene Products, Human Immunodeficiency Virus / chemistry
  • tat Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • RNA, Viral
  • tat Gene Products, Human Immunodeficiency Virus