Abstract
One of the tenets of molecular biology is that dynamic transitions between three-dimensional structures determine the function of proteins. Therefore, it seems only natural that evolutionary analysis of proteins, presently based mainly on their primary sequence, needs to shift its focus toward their function as assessed by corresponding structural transitions. This can be facilitated by recent progress in cryogenic electron microscopy that provides atomic structures of multiple conformational states for proteins and protein assemblies isolated from evolutionarily related species. In this work, we study evolutionary conservation of multiprotein assembly function by using mechanical strain as a quantitative footprint of structural transitions. We adopt the formalism of finite strain theory, developed in condensed matter physics, and apply it, as a case study, to a classical multiprotein assembly, the ATP synthase. Protein strain analysis provides a precise characterization of rotation domains that agrees with the present biophysical knowledge. In addition, we obtain a strain distribution on the protein structure associated with functional transitions. By analyzing in detail the strain patterns of the chains responsible for ATP synthesis across distinct species, we show that they are evolutionarily conserved for the same functional transition. Such conservation is not revealed by displacement or rotation patterns. Furthermore, within each functional transition, we can identify conserved strain patterns for ATP synthases isolated from different organisms. The observed strain conservation across evolutionary distant species indicates that strain should be essential in future structure-based evolutionary studies of protein function.
- Received 18 July 2023
- Revised 10 January 2024
- Accepted 29 January 2024
DOI:https://doi.org/10.1103/PhysRevX.14.011042
Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.
Published by the American Physical Society
Physics Subject Headings (PhySH)
Focus
FocusHow to Compare Proteins
Published 8 March 2024
The motions within the molecule provide a new way to compare the structures and functions of similar proteins.
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Popular Summary
Proteins are nanometer-scale molecules that perform diverse functions by deforming their structure. Many protein structures have been determined with exquisite atomic-level resolution. Yet, despite the wealth of available data, comparative analysis of structures is predominantly guided by visual inspection. Here, we apply the concept of mechanical strain, key in describing elastic deformations of large objects, to the molecular scale of protein and multiprotein complexes.
Our protein strain analysis (PSA) enables novel quantitative analysis of structural changes in proteins, and therefore opens an additional window into the study of protein function. Taking as an example the multiprotein complex that synthesizes ATP, the energy-carrying molecule in all cells, we show that PSA not only quantifies structural changes, but also reveals that mechanical strain is an evolutionarily conserved characteristic of protein function. Such conservation is not revealed by simple metrics, such as displacement or rotation patterns. Furthermore, within each functional transition, we identify conserved strain patterns for ATP synthases isolated from different organisms.
The observed strain conservation across evolutionary distant species indicates that strain should be essential in future structure-based evolutionary studies of protein function.
