Chapter 5
Probing Allosteric Mechanism with Long-Range Rigidity
Transmission Across Protein Networks
Adnan Sljoka
Abstract
Allosteric transmission refers to regulation of protein function at a distance. “Allostery” involves regulation
and/or signal transduction induced by a perturbation event. Allostery, which has been coined the “second
secret of life,” is a fundamental property of most dynamics proteins. Most of critical questions surrounding
allostery are largely unresolved. One of the key puzzles is to describe the physical mechanism of distant
coupled conformational change. Another hot research area surrounding allostery is detection of allosteric
pathways or regions (residues) in the protein that are the most critical for transmission of allosteric
information. Using techniques inspired by mathematical rigidity theory and mechanical linkages, we have
previously proposed a mechanistic model and description of allosteric transmission and an accompanying
computational method, the Rigidity Transmission Allostery (RTA) algorithm. The RTA algorithm and
method are designed to predict if mechanical perturbation of rigidity, for example, due to ligand binding, at
one site of the protein can transmit and propagate across a protein structure and in turn cause a change in
available conformational degrees of freedom and a change in conformation at a second distant site,
equivalently resulting in allosteric transmission. The RTA algorithm is computationally very fast and can
rapidly scan many unknown sites for allosteric transmission, identifying potential novel allosteric sites and
quantify their allosteric effect. In this chapter we will discuss the rigidity-based mechanistic model of
allosteric communication. As a case illustrative study, we will demonstrate RTA analysis on a G protein
coupled receptor (GPCR) human adenosine A 2A receptor. Our method gives important implications and a
novel prospective for general mechanistic description of allosteric communication.
Key words Allostery, Protein flexibility, Degrees of freedom, Rigidity theory, Big data, Pebble game
algorithm, Molecular theorem, FIRST, Rigidity-transmission allostery, RTA algorithm
Abbreviations
DOF
Degrees of freedom
FIRST
Floppy inclusions and rigid substructure topography
GPCR
G protein coupled receptor
PDB
Protein Data Bank
RTA algorithm Rigidity transmission allostery algorithm
TM
Transmembrane
Luisa Di Paola and Alessandro Giuliani (eds.), Allostery: Methods and Protocols, Methods in Molecular Biology, vol. 2253,
https://doi.org/10.1007/978-1-0716-1154-8_5, © Springer Science+Business Media, LLC, part of Springer Nature 2021
61
Probing Allosteric Mechanism with Long-Range Rigidity
Transmission Across Protein Networks
Adnan Sljoka
Abstract
Allosteric transmission refers to regulation of protein function at a distance. “Allostery” involves regulation
and/or signal transduction induced by a perturbation event. Allostery, which has been coined the “second
secret of life,” is a fundamental property of most dynamics proteins. Most of critical questions surrounding
allostery are largely unresolved. One of the key puzzles is to describe the physical mechanism of distant
coupled conformational change. Another hot research area surrounding allostery is detection of allosteric
pathways or regions (residues) in the protein that are the most critical for transmission of allosteric
information. Using techniques inspired by mathematical rigidity theory and mechanical linkages, we have
previously proposed a mechanistic model and description of allosteric transmission and an accompanying
computational method, the Rigidity Transmission Allostery (RTA) algorithm. The RTA algorithm and
method are designed to predict if mechanical perturbation of rigidity, for example, due to ligand binding, at
one site of the protein can transmit and propagate across a protein structure and in turn cause a change in
available conformational degrees of freedom and a change in conformation at a second distant site,
equivalently resulting in allosteric transmission. The RTA algorithm is computationally very fast and can
rapidly scan many unknown sites for allosteric transmission, identifying potential novel allosteric sites and
quantify their allosteric effect. In this chapter we will discuss the rigidity-based mechanistic model of
allosteric communication. As a case illustrative study, we will demonstrate RTA analysis on a G protein
coupled receptor (GPCR) human adenosine A 2A receptor. Our method gives important implications and a
novel prospective for general mechanistic description of allosteric communication.
Key words Allostery, Protein flexibility, Degrees of freedom, Rigidity theory, Big data, Pebble game
algorithm, Molecular theorem, FIRST, Rigidity-transmission allostery, RTA algorithm
Abbreviations
DOF
Degrees of freedom
FIRST
Floppy inclusions and rigid substructure topography
GPCR
G protein coupled receptor
PDB
Protein Data Bank
RTA algorithm Rigidity transmission allostery algorithm
TM
Transmembrane
Luisa Di Paola and Alessandro Giuliani (eds.), Allostery: Methods and Protocols, Methods in Molecular Biology, vol. 2253,
https://doi.org/10.1007/978-1-0716-1154-8_5, © Springer Science+Business Media, LLC, part of Springer Nature 2021
61