Pharma Focus Asia

The Properties of Human Disease Mutations at Protein Interfaces

Benjamin J. Livesey, Joseph A. Marsh

The assembly of proteins into complexes and their interactions with other biomolecules are often vital for their biological function. While it is known that mutations at protein interfaces have a high potential to be damaging and cause human genetic disease, there has been relatively little consideration for how this varies between different types of interfaces.

Single nucleotide variants (SNVs) are the most common type of human genetic variation. While many SNVs in protein-coding regions of the genome are associated with human disease, the vast majority have no noticeable clinical impact. We have still seen only a fraction of the possible coding SNVs in genetic sequencing studies and most of these remain completely unannotated.

Materials and Methods:

ClinVar and gnomAD databases
To establish sets of pathogenic and benign mutations, we used the ClinVar, downloaded on 2020.08.17, and gnomAD v2.1.1 databases. After filtering for missense variants, we selected only those variants in ClinVar labelled as “pathogenic” and “likely pathogenic”.

Protein structures were downloaded from the Protein Data Bank (PDB) on 2020.05.27. The first biological assembly was used to represent the quaternary structure of each protein, and symmetry assignments were taken directly from the PDB..

Ligand interfaces
Ligand interfaces were classified as ‘cognate’, ‘non-cognate’ or ‘ambiguous’ using the FireDB database of ligand significance. As there were very few ligands in the ambiguous category, we investigated disease enrichments for only cognate and non-cognate ligands.

Solvent accessible surface area
SASA is the area of the protein surface that is accessible to solvent molecules. SASA was calculated for each structure using AREAIMOL.

Citation: Livesey BJ, Marsh JA (2022) The properties of human disease mutations at protein interfaces. PLoSComputBiol 18(2): e1009858.

Editor: Petras J. Kundrotas, University of Kansas, UNITED STATES

Received: August 23, 2021; Accepted: January 24, 2022; Published: February 4, 2022.

Copyright: © 2022 Livesey, Marsh. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Supporting data for this manuscript has been deposited at

Funding: JAM was supported by a Medical Research Council ( Career Development Award (MR/M02122X/1) and is a Lister Institute ( Research Prize Fellow. BJL was supported by a Medical Research Council Precision Medicine Doctoral Training Programme studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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