The Evolution of Local Energetic Frustration in Protein Families

Abstract

Energetic local frustration offers a biophysical perspective to interpret the effects of sequence variability on protein families. Here we present a methodology to analyze local frustration patterns within protein families that allows us to uncover constraints related to stability and function, and identify differential frustration patterns in families with a common ancestry. We have analyzed these signals in very well studied cases such as PDZ, SH3, alpha and beta globins and RAS families. Recent advances in protein structure prediction make it possible to analyze a vast majority of the protein space. An automatic and unsupervised proteome-wide analysis on the SARS-CoV-2 virus demonstrates the potential of our approach to enhance our understanding of the natural phenotypic diversity of protein families beyond single protein instances. We have applied our method to modify biophysical properties of natural proteins based on their family properties, as well as perform unsupervised analysis of large datasets to shed light on the physicochemical signatures of poorly characterized proteins such as emergent pathogens.

3Dmapper: A Command Line Tool For BioBank-scale Mapping Of Variants To Protein Structures

“…These alterations, involving a change from a basic to a polar amino acid at position 86 and from an acidic to a polar amino acid at position 97, could have the potential to disrupt the proper protein interaction, highlighting a possible functional significance. Other analyses highlighting the potential of 3Dmapper in different contexts can be found in recent publications, such as the analysis of somatic mutations in interfaces and their effects in disrupting protein protein interactions using data from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) 25 , or the analysis of evolutionary relevant positions across protein families mapped onto reference structures to analyze their local energetics, known as “frustration”, adding a layer of understanding to protein evolution dynamics 26 .…”

Frustraevo: A Web Server To Localize And Quantify The Conservation Of Local Energetic Frustration In Protein Families

“…The FrustraEvo web server implements a methodology that we have recently described to quantify the conservation of local energetic frustration in protein families 10 . Residues whose frustration states are conserved in a majority of homologous proteins suggest the presence of selective pressure to maintain such a state.…”

“…Only columns in the MSA that are not gaps in the reference protein are considered. More details can be found in 10 . Finally, users can provide their email address to be notified when the job is completed.…”

“…Since AlphaFold2 was released, high quality structural models are available for a large majority of known proteins. Fueled by this availability, we have recently proposed a methodology to exploit the evolutionary information that is harbored within sets of homologous proteins, to identify energetic features of protein families that facilitate the biophysical understanding of a family and its individual members 10 . Features that are common to a majority of family members can be interpreted as evolutionary conserved constraints.…”

Predicting the dynamic interaction of intrinsically disordered proteins

“…The frustration index at contact level is calculated for each residue-residue contact present in a protein structure, which is a statistical measure of how energetically favorable a native contact is with respect to a set of all possible contacts at that location. A recent study showed that local frustration is an evolutionary constraint that is related to protein stability and function 71 . As indicated in previous studies, residues involved in PPIs are enriched with highly frustrated contacts [72][73][74][75] , suggesting the frustration index may be a suitable feature for PPI prediction.…”