1 Introduction
Allosteric control of protein function refers to regulation at a
distance. Allostery is one of the most powerful and predominant
means of regulating protein activity and has been referred to as “the
second secret of life.” [1]. Allosteric regulation is a universal phenomenon that is initiated by a perturbation through binding of an
effector molecule at an allosteric site that is topographically distinct
and remote from orthosteric/active binding site. Binding of an
effector molecule at the allosteric site(s) triggers a local conformational change that can propagate a substantial distance to cause a
rearrangement and a change in conformation and dynamics at a
distant functional active site, subsequently resulting in modification
of protein function. Allostery is a common event in a cell and it
occurs in all dynamics proteins, in RNA and DNA polymers [2–4].
Initial perturbation can arise due to covalent (i.e., phosphorylation,
enzyme-substrate reaction, point mutation) and noncovalent
(binding of drugs, proteins, ions, etc.) modifications at the allosteric site [2]. It is integral to the control of metabolic and signaling
pathways, and it provides organisms the ability to adapt to constant
changes in cellular and environmental conditions [1–4]. As allosteric interactions at a remote site lead to conformational and ultimately a change in functional site and deregulation of a protein
function, allostery has direct relevance to cellular function and
disease [2]. Remarkably, even after 50 years since the concept of
allostery was first introduced [5], most of the critical questions
surrounding allostery remain unresolved. One of the key puzzles
is to provide a mechanistic description of allosteric transmission
between remote sites in a protein, specifically how a structural
change in conformation at an allosteric site (in some cases a subtle
change) can induce a change in conformation at a distant active site.
Moreover, what region in the protein is important for allosteric
transmission (i.e., what are the allosteric pathways?). Since allostery
is a crucial biological phenomenon for understanding biological
systems, disease, and design of novel allosteric drugs, decoding the
mechanism of allosteric transmission remains one of the key longstanding unsolved problems in biological sciences.
In this chapter we describe and summarize the mechanistic
description and physical model for allosteric transmission called
Rigidity Transmission Allostery (RTA) analysis. RTA is based on
concepts in mathematical rigidity theory [6, 7] building on our
initial work on mathematical models and algorithms for studying
allostery [8] with further theoretical considerations in [9]. We will
demonstrate the RTA analysis on a crystal structure of a GPCR
receptor. RTA algorithm was recently used to predict and quantify
allosteric interactions between remote sites in protein structures
62
Adnan Sljoka
Allosteric control of protein function refers to regulation at a
distance. Allostery is one of the most powerful and predominant
means of regulating protein activity and has been referred to as “the
second secret of life.” [1]. Allosteric regulation is a universal phenomenon that is initiated by a perturbation through binding of an
effector molecule at an allosteric site that is topographically distinct
and remote from orthosteric/active binding site. Binding of an
effector molecule at the allosteric site(s) triggers a local conformational change that can propagate a substantial distance to cause a
rearrangement and a change in conformation and dynamics at a
distant functional active site, subsequently resulting in modification
of protein function. Allostery is a common event in a cell and it
occurs in all dynamics proteins, in RNA and DNA polymers [2–4].
Initial perturbation can arise due to covalent (i.e., phosphorylation,
enzyme-substrate reaction, point mutation) and noncovalent
(binding of drugs, proteins, ions, etc.) modifications at the allosteric site [2]. It is integral to the control of metabolic and signaling
pathways, and it provides organisms the ability to adapt to constant
changes in cellular and environmental conditions [1–4]. As allosteric interactions at a remote site lead to conformational and ultimately a change in functional site and deregulation of a protein
function, allostery has direct relevance to cellular function and
disease [2]. Remarkably, even after 50 years since the concept of
allostery was first introduced [5], most of the critical questions
surrounding allostery remain unresolved. One of the key puzzles
is to provide a mechanistic description of allosteric transmission
between remote sites in a protein, specifically how a structural
change in conformation at an allosteric site (in some cases a subtle
change) can induce a change in conformation at a distant active site.
Moreover, what region in the protein is important for allosteric
transmission (i.e., what are the allosteric pathways?). Since allostery
is a crucial biological phenomenon for understanding biological
systems, disease, and design of novel allosteric drugs, decoding the
mechanism of allosteric transmission remains one of the key longstanding unsolved problems in biological sciences.
In this chapter we describe and summarize the mechanistic
description and physical model for allosteric transmission called
Rigidity Transmission Allostery (RTA) analysis. RTA is based on
concepts in mathematical rigidity theory [6, 7] building on our
initial work on mathematical models and algorithms for studying
allostery [8] with further theoretical considerations in [9]. We will
demonstrate the RTA analysis on a crystal structure of a GPCR
receptor. RTA algorithm was recently used to predict and quantify
allosteric interactions between remote sites in protein structures
62
Adnan Sljoka