Allosteric sites can be identified based on the residue-residue interaction energy difference

Abstract

Allosteric drugs act at a distance to regulate protein functions. They have several advantages over conventional orthosteric drugs, including diverse regulation types and fewer side effects. However, the rational design of allosteric ligands remains a challenge, especially when it comes to the identification allosteric binding sites. As the binding of allosteric ligands may induce changes in the pattern of residue-residue interactions, we calculated the residue-residue interaction energies within the allosteric site based on the molecular mechanics generalized Born surface area energy decomposition scheme. Using a dataset of 17 allosteric proteins with structural data for both the apo and the ligand-bound state available, we used conformational ensembles generated by molecular dynamics simulations to compute the differences in the residue-residue interaction energies in known allosteric sites from both states. For all the known sites, distinct interaction energy differences (>25%) were observed. We then used CAVITY, a binding site detection program to identify novel putative allosteric sites in the same proteins. This yielded a total of 31 "druggable binding sites," of which 21 exhibited >25% difference in residue interaction energies, and were hence predicted as novel allosteric sites. Three of the predicted allosteric sites were supported by recent experimental studies. All the predicted sites may serve as novel allosteric sites for allosteric ligand design. Our study provides a computational method for identifying novel allosteric sites for allosteric drug design.

Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery

“…Individual amino acid residues, which are basic building blocks for protein structures, and therefore serve as the main target for many residue based protein allostery analysis methods,[ 47 , 74 – 76 ] in which residue based interaction energy is the target for analysis. However, because protein allostery is mainly considered a dynamical process, it should be informative to investigate the internal dynamics of each individual residue and their impact on overall protein dynamics.…”

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

“…Next, we established a computational scheme to quantify the reversed allosteric communication caused by orthosteric binding and confirmed the coupling between the orthosteric site and the predicted allosteric sites. A previous study established the residue-residue interaction model in which some residue pairs within the allosteric sites exhibited substantial interaction energy changes upon ligand binding 52,60 . Based on this model, we derived a quantitative model to evaluate allosteric coupling between the orthosteric and allosteric sites.…”

Singular value decomposition for the correlation of atomic fluctuations with arbitrary angle

“…An important application of correlation analysis is the prediction of allosteric sites in protein . Thus, we evaluated the effectiveness of the DP and SVD methods in allosteric‐site prediction.…”

“…An important application of correlation analysis is the prediction of allosteric sites in protein. 15,65,[85][86][87] Thus, we evaluated the effectiveness of the DP and SVD methods in allosteric-site prediction. The prediction analysis was conducted similarly to that of Ma et al 65 The allosteric proteins dataset was collected from the Core-Diversity set of ASBench, 88 as mentioned in the previous study.…”

“…Computational methods have characterized the structural/dynamical changes in allosteric proteins and identified their allosteric pathways/sites; the latter is crucial for allosteric drug design. Computational methods for allostery can be roughly classified into two types: sequence‐based and conformation‐based.…”