The circadian clocks play an important role in ecosystems by synchronizing biological processes to cycles of light and temperature. In nature, they are regulated by protein allostery, which is the process that regulates protein functional activities, together with conformational or dynamical changes, upon an external perturbation. Light, oxygen or voltage (LOV) proteins are a circadian clock family that are sensitive to blue light. The conformational-driven allosteric protein, diatom <i>Phaeodactylum tricornutum</i> aureochrome 1a (PtAu1a), belongs to this group, with certain differences from other LOV proteins for its uncommon structural topology. The mechanism of signaling transduction in the PtAu1a LOV domain (AuLOV) including flanking helices remains unclear because of this dissimilarity, which hinders the study of PtAu1a as an optogenetic tool. To clarify this mechanism, we employed a combination of molecular dynamics (MD) simulations, ivis dimensionality reduction method, Markov state models, one-vs-one random forest, machine-learning-based community analysis, and transition path theory to quantitatively analyze the allosteric process. Our results identified several experimentally reported residues that are vital in the allosteric process. We further revealed a previously overlooked Cα helix and protein linkers as important in promoting the protein conformational changes. This integrated approach can be considered as a general workflow and applied on other allosteric proteins to provide detailed information about their allosteric mechanisms.

Machine learning framework for deciphering the allosteric process of circadian clock protein

ACS Spring Meeting 2021

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