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Molecular Forces Governing the Biological Function of Per-Arnt-Sim-B (PAS-B) Domains: A Comparative Computational Study

Chemistry—School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
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These authors contributed equally to this work.
Received: 22 December 2020 / Revised: 5 January 2021 / Accepted: 12 January 2021 / Published: 5 February 2021
Per-Arnt-Sim (PAS) domains are evolutionarily-conserved regions found in proteins in all living systems, involved in transcriptional regulation and the response to hypoxic and xenobiotic stress. Despite having low primary sequence similarity, they show an impressively high structural conservation. Nonetheless, understanding the underlying mechanisms that drive the biological function of the PAS domains remains elusive. In this work, we used molecular dynamics simulations and bioinformatics tools in order the investigate the molecular characteristics that govern the intrinsic dynamics of five PAS-B domains (human AhR receptor, NCOA1, HIF1α, and HIF2α transcription factors, and Drosophila Suzukii (D. Suzukii) juvenile hormone receptor JHR). First, we investigated the effects of different length of N and C terminal regions of the AhR PAS-B domain, showing that truncation of those segments directly affects structural stability and aggregation propensity of the domain. Secondly, using the recently annotated PAS-B located in the methoprene-tolerant protein/juvenile hormone receptor (JHR) from D. Suzukii, we have shown that the mutation of the highly conserved “gatekeeper” tyrosine to phenylalanine (Y322F) does not affect the stability of the domain. Finally, we investigated possible redox-regulation of the AhR PAS-B domain by focusing on the cysteinome residues within PAS-B domains. The cysteines in AhR PAS-B are directly regulating the dynamics of the small molecule ligand-gating loop (residues 305 to 326). In conclusion, we comprehensibly described several molecular features governing the behaviour of PAS-B domains in solution, which may lead to a better understanding of the forces driving their biological functions. View Full-Text
Keywords: Per-Arnt-Sim; molecular dynamics simulations; aryl hydrocarbon receptor; D. Suzukii; NCOA1; HIF1α; HIF2α; cysteinome Per-Arnt-Sim; molecular dynamics simulations; aryl hydrocarbon receptor; D. Suzukii; NCOA1; HIF1α; HIF2α; cysteinome
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MDPI and ACS Style

de Souza, J.V.; Zaborniak, P.; Reznikov, S.; Kondal, M.; Zhu, R.; Bronowska, A.K. Molecular Forces Governing the Biological Function of Per-Arnt-Sim-B (PAS-B) Domains: A Comparative Computational Study. Biophysica 2021, 1, 1-14. https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1010001

AMA Style

de Souza JV, Zaborniak P, Reznikov S, Kondal M, Zhu R, Bronowska AK. Molecular Forces Governing the Biological Function of Per-Arnt-Sim-B (PAS-B) Domains: A Comparative Computational Study. Biophysica. 2021; 1(1):1-14. https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1010001

Chicago/Turabian Style

de Souza, João V., Piotr Zaborniak, Sylvia Reznikov, Matthew Kondal, Ruidi Zhu, and Agnieszka K. Bronowska 2021. "Molecular Forces Governing the Biological Function of Per-Arnt-Sim-B (PAS-B) Domains: A Comparative Computational Study" Biophysica 1, no. 1: 1-14. https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1010001

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