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Compensatory epistasis explored by molecular dynamics simulations

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Abstract

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.

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Fig. 1
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taken from the MD simulations studies on the different FIXa protein variants and the catalytic domain from the crystallographic structure

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Funding

This work was supported by Fundo Europeu de Desenvolvimento Regional (FEDER) through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization, Portugal 2020 and by Foundation for Science and Technology (FCT) [POCI-01-0145-FEDER-007274, POCI-01-0145-FEDER-29723]; Foundation for Science and Technology [UIDB/04423/2020, UIDP/04423/2020, UIDP/04378/2020, UIDB/04378/2020, SFRH/BD/137925/2018 to C.S.]; Infraestrutura Nacional de Computação Distribuída (INCD) [01/SAICT/2016 number 022153, CPCA/A00/7140/2020, CPCA/A00/7145/2020] through funds from Foundation for Science and Technology and Fundo Europeu de Desenvolvimento Regional; Foundation for Science and Technology [under the transitional rule of Decree Law 57/2016, amended by Law 57/2017 to J.C.]; Foundation for Science and Technology [2020.01423.CEECIND to S.S.].

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  1. Sérgio F. Sousa and Luísa Azevedo contributed equally to this manuscript.

Authors and Affiliations

  1. i3S, Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal

    Catarina Serrano, Mónica Lopes-Marques, António Amorim, Maria J. Prata & Luísa Azevedo

  2. IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal

    Catarina Serrano, Mónica Lopes-Marques, António Amorim, Maria J. Prata & Luísa Azevedo

  3. Department of Biology, Faculty of Sciences, University of Porto, Rua Do Campo Alegre, s/n, 4169-007, Porto, Portugal

    Catarina Serrano, Mónica Lopes-Marques, António Amorim, Maria J. Prata & Luísa Azevedo

  4. UCIBIO/REQUIMTE, BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal

    Carla S. S. Teixeira & Sérgio F. Sousa

  5. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK

    David N. Cooper & Peter D. Stenson

  6. CIIMAR, Interdisciplinary Centre of Marine and Environmental Research, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos, s/n, 4450-208, Matosinhos, Portugal

    João Carneiro

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  1. Catarina Serrano
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  2. Carla S. S. Teixeira
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  9. Sérgio F. Sousa
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Correspondence to Sérgio F. Sousa or Luísa Azevedo.

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Sequences used in this study were retrieved from the Ensembl Genome Browser (https://www.ensembl.org) and are shown in Supplementary Table S1. Human disease-causing missense variants were retrieved from HGMD (http://www.hgmd.cf.ac.uk). The crystal structure of FIXa (6MV4) and GLA (3S5Z) were retrieved from the Protein Data Bank (PDB) (https://www.rcsb.org).

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Serrano, C., Teixeira, C.S.S., Cooper, D.N. et al. Compensatory epistasis explored by molecular dynamics simulations. Hum Genet 140, 1329–1342 (2021). https://doi.org/10.1007/s00439-021-02307-x

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