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Compensatory epistasis explored by molecular dynamics simulations

Serrano, Catarina, Teixeira, Carla S. S., Cooper, David N. ORCID:, Carneiro, João, Lopes-Marques, Mónica, Stenson, Peter D., Amorim, António, Prata, Maria J., Sousa, Sérgio F. and Azevedo, Luísa 2021. Compensatory epistasis explored by molecular dynamics simulations. Human Genetics 140 (9) , pp. 1329-1342. 10.1007/s00439-021-02307-x

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A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms of compensatory epistasis can alleviate the mutations’ otherwise pathogenic effects. Examples of compensated variants have been described in the literature but the interacting residue(s) postulated to play a compensatory role have rarely been ascertained. In this study, the examination of five human X-chromosomally encoded proteins (FIX, GLA, HPRT1, NDP and OTC) allowed us to identify several candidate compensated variants. Strong evidence for a compensated/compensatory pair of amino acids in the coagulation FIXa protein (involving residues 270 and 271) was found in a variety of mammalian species. Both amino acid residues are located within the 60-loop, spatially close to the 39-loop that performs a key role in coagulation serine proteases. To understand the nature of the underlying interactions, molecular dynamics simulations were performed. The predicted conformational change in the 39-loop consequent to the Glu270Lys substitution (associated with hemophilia B) appears to impair the protein’s interaction with its substrate but, importantly, such steric hindrance is largely mitigated in those proteins that carry the compensatory residue (Pro271) at the neighboring amino acid position.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Springer
ISSN: 0340-6717
Date of First Compliant Deposit: 14 September 2021
Date of Acceptance: 20 June 2021
Last Modified: 10 Nov 2022 23:12

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