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Energy landscapes in molecular biology: History, principles, and perspectives

Published online by Cambridge University Press:  22 April 2026

Ruth Nussinov*
Affiliation:
Biophysics and Computational Biology Section, Frederick National Laboratory for Cancer Research , Frederick, MD 21702, USA Cancer Innovation Laboratory, National Cancer Institute Frederick , Frederick, MD 21702, USA Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University , Tel Aviv 69978, Israel
Clil Regev
Affiliation:
Cancer Innovation Laboratory, National Cancer Institute Frederick , Frederick, MD 21702, USA
Hyunbum Jang
Affiliation:
Biophysics and Computational Biology Section, Frederick National Laboratory for Cancer Research , Frederick, MD 21702, USA Cancer Innovation Laboratory, National Cancer Institute Frederick , Frederick, MD 21702, USA
*
Corresponding author: Ruth Nussinov; Email: nussinor@mail.nih.gov

Abstract

In an editorial for a Special Issue, Nussinov and Wolynes explored the energy landscapes of biomolecular function, questioning whether they constituted a second molecular biology revolution. With more than a decade having passed and science having progressed significantly, we revisit this question. Statistical energy landscapes not only visualize folding funnels but also quantify the likelihoods of different states, embodying the foundational physical-chemical principles of protein actions. Building upon the theory of energy landscapes, the conformational selection and population shift paradigm posited that since all functional conformations already pre-exist in a dynamic equilibrium, a ligand ‘selects’ and stabilizes a state from this pre-existing pool, resulting in re-equilibration, or shift, of the population. The principle that it established — that function harnesses transitions between pre-existing conformations — revolutionized the understanding of allostery and, broadly, regulation. This paradigm challenged and superseded the decades-old, albeit persisting, belief of only one (or two; ‘open’ and ‘closed’) protein conformations. It also indicates that for engineered proteins to exert effective function, we must account for the timescales of flipping between energy landscape states, for example, by tuning the barrier heights. Returning to the question of whether landscapes constituted a second biomolecular biology revolution, we consider their bedrock contributions, which are far beyond the original protein folding funnels. They established the principle of multiple dynamic conformational states ‘jumping’ over barriers during population shifts. By leveraging core concepts like conformational ensembles, modern molecular biology has achieved breakthroughs such as next-generation allosteric drugs, indeed leading to a transformative era in molecular science.

Information

Type
Review
Creative Commons
This is a work of the US Government and is not subject to copyright protection within the United States. Published by Cambridge University Press.
Copyright
© National Institutes of Health, 2026

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