Abstract
Protein structure and protein function should be related, yet the nature of this relationship remains unsolved. Mapping the critical residues for protein function with protein structure features represents an opportunity to explore this relationship, yet two important limitations have precluded a proper analysis of the structure-function relationship of proteins: (i) the lack of a formal definition of what critical residues are and (ii) the lack of a systematic evaluation of methods and protein structure features. To address this problem, here we introduce an index to quantify the protein-function criticality of a residue based on experimental data and a strategy aimed to optimize both, descriptors of protein structure (physicochemical and centrality descriptors) and machine learning algorithms, to minimize the error in the classification of critical residues. We observed that both physicochemical and centrality descriptors of residues effectively relate protein structure and protein function, and that physicochemical descriptors better describe critical residues. We also show that critical residues are better classified when residue criticality is considered as a binary attribute (i.e., residues are considered critical or not critical). Using this binary annotation for critical residues 8 models rendered accurate and non-overlapping classification of critical residues, confirming the multi-factorial character of the structure-function relationship of proteins.
Highlights
The study of the relationship between protein structure and protein function constitutes an open problem in biochemistry and bioinformatics
Our work aims to first test which descriptors of protein structure are relevant to classify critical residues for protein function; for this goal we used different definitions of critical residues for protein function previously reported in the literature
The first set was the one previously described by our group to predict critical residues for protein function based on centralities [16]; this set included 6 proteins that classified critical or not criticalcritical residues according to function the different criterion reported described by our group to predict residues for protein based on centralities
Summary
The study of the relationship between protein structure and protein function constitutes an open problem in biochemistry and bioinformatics. Given the accumulation of protein sequences most efforts to predict protein function are based on this information. The mechanisms of protein function are studied based on the atomic three-dimensional structure of proteins (hereafter referred to as protein structure). Despite this difference in the data source, these two approaches converge in the prediction of critical residues for protein function revealing the relevance of this subject [1]. Critical residues may be ones critical for protein stability, folding, binding and/or catalysis performed by the protein of interest, these residues hold key information to understand the structure-function relationship of proteins
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