UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Interpreting the effect of mutations to protein binding sites from large-scale genomic screens

Jamshidi Parvar, Sara; Hall, Benjamin A; Shorthouse, David; (2024) Interpreting the effect of mutations to protein binding sites from large-scale genomic screens. Methods , 222 122--132. 10.1016/j.ymeth.2023.12.008. Green open access

[thumbnail of 1-s2.0-S1046202323002207-main.pdf]
Preview
Text
1-s2.0-S1046202323002207-main.pdf - Published Version

Download (3MB) | Preview

Abstract

redicting the functionality of missense mutations is extremely difficult. Large-scale genomic screens are commonly performed to identify mutational correlates or drivers of disease and treatment resistance, but interpretation of how these mutations impact protein function is limited. One such consequence of mutations to a protein is to impact its ability to bind and interact with partners or small molecules such as ATP, thereby modulating its function. Multiple methods exist for predicting the impact of a single mutation on protein–protein binding energy, but it is difficult in the context of a genomic screen to understand if these mutations with large impacts on binding are more common than statistically expected. We present a methodology for taking mutational data from large-scale genomic screens and generating functional and statistical insights into their role in the binding of proteins both with each other and their small molecule ligands. This allows a quantitative and statistical analysis to determine whether mutations impacting protein binding or ligand interactions are occurring more or less frequently than expected by chance. We achieve this by calculating the potential impact of any possible mutation and comparing an expected distribution to the observed mutations. This method is applied to examples demonstrating its ability to interpret mutations involved in protein–protein binding, protein-DNA interactions, and the evolution of therapeutic resistance.

Type: Article
Title: Interpreting the effect of mutations to protein binding sites from large-scale genomic screens
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ymeth.2023.12.008
Publisher version: https://doi.org/10.1016/j.ymeth.2023.12.008
Language: English
Keywords: Binding calculations, FoldX, Protein structure, Missense mutation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: https://discovery.ucl.ac.uk/id/eprint/10185905
Downloads since deposit
42Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item