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. 2024 Jul 9;20(13):5774-5783.
doi: 10.1021/acs.jctc.4c00454. Epub 2024 Jun 25.

Machine Learning Derived Collective Variables for the Study of Protein Homodimerization in Membrane

Ayan Majumder  1 , John E Straub  1
Affiliations

Machine Learning Derived Collective Variables for the Study of Protein Homodimerization in Membrane

Ayan Majumder et al. J Chem Theory Comput. .

Abstract

The accurate calculation of equilibrium constants for protein-protein association is of fundamental importance to quantitative biology and remains an outstanding challenge for computational biophysics. Traditionally, equilibrium constants have been computed from one-dimensional free energy surfaces derived from sampling along a single collective variable. Importantly, recent advances in enhanced sampling methodology have facilitated the characterization of multidimensional free energy landscapes, often exposing multiple thermodynamically important minima missed by more restrictive sampling methods. A key to the effectiveness of this multidimensional sampling approach is the identification of collective variables that effectively define the configurational space of dissociated and associated states. Here we present the application of two machine learning methods for the unbiased determination of collective variables for enhanced sampling and analysis of protein-protein association. Our results both validate prior work, based on intuition derived collective variables, and demonstrate the effectiveness of the machine learning methods for the identification of collective variables for association reactions in complex biomolecular systems.

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Conflict of interest statement

The authors declare no competing financial interest.

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References

    1. Engel A; Gaub HE Structure and mechanics of membrane proteins. Annu. Rev. Biochem. 2008, 77, 127–148. - PubMed
    1. Majumder A; Vuksanovic N; Ray LC; Bernstein HM; Allen KN; Imperiali B; Straub JE Synergistic computational and experimental studies of a phosphoglycosyltransferase membrane/ligand ensemble. J. Biol. Chem. 2023, 299, 105194. - PMC - PubMed
    1. Gomes I; Ayoub MA; Fujita W; Jaeger WC; Pfleger KD; Devi LA G protein-coupled receptor heteromers. Annual review of pharmacology and toxicology 2016, 56, 403–425. - PMC - PubMed
    1. Irvine GB; El-Agnaf OM; Shankar GM; Walsh DM Protein aggregation in the brain: the molecular basis for Alzheimer’s and Parkinson’s diseases. Molecular medicine 2008, 14, 451–464. - PMC - PubMed
    1. Nguyen PH; Ramamoorthy A; Sahoo BR; Zheng J; Faller P; Straub JE; Dominguez L; Shea J-E; Dokholyan NV; De Simone A; et al. Amyloid oligomers: A joint experimental/computational perspective on Alzheimer’s disease, Parkinson’s disease, type II diabetes, and amyotrophic lateral sclerosis. Chem. Rev. 2021, 121, 2545–2647. - PMC - PubMed

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