Coding mutations can affect many aspects of a protein's structure and function, including its interactions with other molecules. Understanding these effects provides invaluable insights into genetic diseases, drug resistance and protein engineering. While there are many tools available to analyze and predict how a mutation might alter protein structure and function, these are all limited by either not providing any mechanistic insight, or by focussing on specific molecular consequences. In order to fully interpret the effect of a mutation, one must consider the full range of potential molecular consequences.
Here we present a novel integrated tool for the analysis of coding missense mutations, which easily and rapidly facilitates the analysis of the effects of mutations on all aspects of the protein structures and functionalities using available structural information. The server accepts a protein structure file to analyse either a given list of mutations, or to perform saturation alanine mutagenesis. We then leverage the tools SDM2, mCSM-Stability and DUET to assess the impact of each mutation on protein folding and stability; mCSM-PPI, mCSM-NA2 and mCSM-lig to analyse the effect of each mutation on protein interactions; which are combined with structural analyses of conservation, electrostatics, flexibility calculated using Encomm and molecular interactions calculated using Arpeggio. The results are presented through an interface that provides a machine learned interpretation of the results based upon the predictions normalised to the protein of interest. The raw data along with pymol session files to enable ready visualisation of each result are made available for download.
This presents the first fully integrated structural based mutation analysis platform, and will be an invaluable resource for researchers analyzing the effects of mutations at the bench and in the clinic.