Prediction of allosteric sites on protein surfaces with an elastic-network-model-based thermodynamic method

Abstract

Allostery is a rapid and efficient way in many biological processes to regulate protein functions, where binding of an effector at the allosteric site alters the activity and function at a distant active site. Allosteric regulation of protein biological functions provides a promising strategy for novel drug design. However, how to effectively identify the allosteric sites remains one of the major challenges for allosteric drug design. In the present work, a thermodynamic method based on the elastic network model was proposed to predict the allosteric sites on the protein surface. In our method, the thermodynamic coupling between the allosteric and active sites was considered, and then the allosteric sites were identified as those where the binding of an effector molecule induces a large change in the binding free energy of the protein with its ligand. Using the proposed method, two proteins, i.e., the 70 kD heat shock protein (Hsp70) and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, were studied and the allosteric sites on the protein surface were successfully identified. The predicted results are consistent with the available experimental data, which indicates that our method is a simple yet effective approach for the identification of allosteric sites on proteins.

AIM for Allostery: Using the Ising Model to Understand Information Processing and Transmission in Allosteric Biomolecular Systems

“…Efforts to identify allosteric sites and channels in the structures of functional biomolecules have utilized estimates of correlation or mutual information between the structural dynamics of known allosteric sites and candidate modulation sites or channels, most often based on the analysis of molecular dynamics (MD) trajectories [ 33 , 34 , 18 , 19 ] or elastic network models (ENMs) [ 35 , 36 ]. Equation ( 43 ) indicates that structural components that can act as channels will have high effective interaction energy with known allosteric sites (e.g., ), and the Shannon-Hartley theorem, ( 8 ), suggests that the allosteric efficacy can be related to the mutual information via the channel capacity.…”

Controlling Allosteric Networks in Proteins

“…The anisotropic network model , uses the Cartesian coordinates of C α atoms to construct the Hessian matrix, and is essentially a course-grained normal-mode analysis similar to that originally constructed by Hinsen . Normal-mode analysis has been widely employed for detecting allosteric sites , and mapping allosteric pathways ,, in biological molecules.…”

A Time-Dependent Quantum Approach to Allostery and a Comparison With Light-Harvesting in Photosynthetic Phenomenon

“…Another approach to studying coupled motions at the time scales required for understanding protein functioning is by using normal-mode analysis (Tasumi et al, 1982;Go et al, 1983;Bahar and Rader, 2005;Ma, 2005;Skjaerven et al, 2009). This analysis has been widely employed for detecting allosteric sites (Sethi et al, 2009;Su et al, 2014) and mapping allosteric pathways. Of course, normal-modes analysis has often been performed with classical mechanics, as in MD simulations, while, as we have already stated, the main aim of this paper is to go beyond a classical mechanics approximation.…”