Discarding Functional Residues from the Substitution Table Improves Predictions of Active Sites within Three-Dimensional Structures

Abstract

Substitutions of individual amino acids in proteins may be under very different evolutionary restraints depending on their structural and functional roles. The Environment Specific Substitution Table (ESST) describes the pattern of substitutions in terms of amino acid location within elements of secondary structure, solvent accessibility, and the existence of hydrogen bonds between side chains and neighbouring amino acid residues. Clearly amino acids that have very different local environments in their functional state compared to those in the protein analysed will give rise to inconsistencies in the calculation of amino acid substitution tables. Here, we describe how the calculation of ESSTs can be improved by discarding the functional residues from the calculation of substitution tables. Four categories of functions are examined in this study: protein–protein interactions, protein–nucleic acid interactions, protein–ligand interactions, and catalytic activity of enzymes. Their contributions to residue conservation are measured and investigated. We test our new ESSTs using the program CRESCENDO, designed to predict functional residues by exploiting knowledge of amino acid substitutions, and compare the benchmark results with proteins whose functions have been defined experimentally. The new methodology increases the Z-score by 98% at the active site residues and finds 16% more active sites compared with the old ESST. We also find that discarding amino acids responsible for protein–protein interactions helps in the prediction of those residues although they are not as conserved as the residues of active sites. Our methodology can make the substitution tables better reflect and describe the substitution patterns of amino acids that are under structural restraints only.

Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Matrix Proteins Specify Different Capabilities To Modulate B Cell Growth

“…The absence of constraints in H5 does not limit the number and location of mutations that can be accepted per replication cycle (61). This is in agreement with several phylogenetic studies tracing the degree of HIV-1 evolution which showed that protein structure constrains evolutionary change in HIV-1 and that the surface of a protein is more likely to accept replacements than the compact core (62,63). Based on the change of the H5 region from a ␤-sheet in SIV MA to an ␣-helix in p17, we can hypothesize that there has been a functional change to a dramatic change in protein function.…”

Sequence and structural analysis of binding site residues in protein–protein complexes

“…These methods are mainly based on surface patches, combination of sequence and structure features including solvent accessibility, protrusion and depth, environment specific substitution tables, multiple sequence alignment, conserved physical-chemical interactions, positional weight matrices and machine learning techniques [10][11][12][13][14][15][16][17][18][19][20].…”

Constraints on HIV-1 Diversity from Protein Structure

“…In addition, the relationship between the cytotoxic T lymphocyte (CTL) response, sequence diversity, and protein secondary structure has been studied (55). It may be expected that protein structure constrains evolutionary change in HIV, since this has been demonstrated in other systems (12,19,31,35,36). For example, it has been shown that the core of a protein is less likely to accept replacements than the surface and that different secondary structure types and hydrogen-bonding classes accept different replacements (19,35).…”