Entropic control of the free-energy landscape of an archetypal biomolecular machine

Journal Article · 15 May 2023 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.2220591120 · OSTI ID:1973697

Ray, Korak Kumar  ^[1]; Kinz-Thompson, Colin D.  ^[1]; Fei, Jingyi  ^[1]; Wang, Bin ^[2]; Lin, Qiao ^[2]; Gonzalez, Ruben L.  ^[1]

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1. Department of Chemistry, Columbia University, New York, NY 10027
2. Department of Mechanical Engineering, Columbia University, New York, NY 10027

Biomolecular machines are complex macromolecular assemblies that utilize thermal and chemical energy to perform essential, multistep, cellular processes. Despite possessing different architectures and functions, an essential feature of the mechanisms of action of all such machines is that they require dynamic rearrangements of structural components. Surprisingly, biomolecular machines generally possess only a limited set of such motions, suggesting that these dynamics must be repurposed to drive different mechanistic steps. Although ligands that interact with these machines are known to drive such repurposing, the physical and structural mechanisms through which ligands achieve this remain unknown. Using temperature-dependent, single-molecule measurements analyzed with a time-resolution-enhancing algorithm, here, we dissect the free-energy landscape of an archetypal biomolecular machine, the bacterial ribosome, to reveal how its dynamics are repurposed to drive distinct steps during ribosome-catalyzed protein synthesis. Specifically, we show that the free-energy landscape of the ribosome encompasses a network of allosterically coupled structural elements that coordinates the motions of these elements. Moreover, we reveal that ribosomal ligands which participate in disparate steps of the protein synthesis pathway repurpose this network by differentially modulating the structural flexibility of the ribosomal complex (i.e., the entropic component of the free-energy landscape). We propose that such ligand-dependent entropic control of free-energy landscapes has evolved as a general strategy through which ligands may regulate the functions of all biomolecular machines. Such entropic control is therefore an important driver in the evolution of naturally occurring biomolecular machines and a critical consideration for the design of synthetic molecular machines.

• Research Organization: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
• Sponsoring Organization: USDOE
• Grant/Contract Number: AC05-06OR23100; AC02-76SF00515
• OSTI ID: 1973697
• Alternate ID(s): OSTI ID: 2423902
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Vol. 120 Journal Issue: 21; ISSN 0027-8424
• Publisher: Proceedings of the National Academy of SciencesCopyright Statement
• Country of Publication: United States
• Language: English