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  • Open Access

Physical principles of building protein megacomplexes in a crowded milieu

Jiayi Wang1, Jules Nde2, Andrei G. Gasic3, Jacob Haseley1, and Margaret S. Cheung1,4,*

  • *Contact author: margaret.cheung@pnnl.gov
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Phys. Rev. Research 8, 033320 – Published 15 September, 2026

DOI: https://doi.org/10.1103/b8cy-vfy5

Abstract

Multiple phenotypic protein expressions arise from one genome represent variations in the protein relative abundance and their stoichiometry. A lack of definite compositional parts challenges the modeling of protein megacomplexes and cellular architectures. Despite the advance in protein structural predictions with Artificial Intelligence (AI), the mechanism of protein interactions and the emergence of megacomplexes they assemble remains unclear. Here, we present a statistical-physics framework of grand canonical ensemble to explore the protein interactions that drive the emergent assembly of a megacomplex using the observational mass spectrometry datasets including protein relative abundance and the cross-linked connections. Using chromatin remodeler megacomplex, INO80, as an example, we discovered a class of “divergent” protein that plays a critical role in orchestrating the assembly beyond nearest neighbors, dependent on the excluded volumes exerted by others. With the constraints of the excluded volumes by varying the volume fraction of INO80 subunits, these divergent subunits orchestrate and form clusters with selective components growing into configurationally distinct architectures. We propose a machinery view for the INO80 chromatin remodeler complex where each loosely associated subunits can be occasionally recruited for parts as attachment into a core assembly driven by excluded volumes. Our computational framework provides a mechanistic insight into taking the volume fractions as necessary physicochemical variables representing cell states to remodel the configurations of protein megacomplexes with structurally loose modules.

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Phys. Rev. Research 8, 033320– Published 15 September, 2026
  • Received 15 February 2026
  • Accepted 8 August 2026
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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.

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