Computational approaches to mapping allosteric pathways

Feher, Victoria A.; Durrant, Jacob D.; Wart, Adam T. Van; Amaro, Rommie E.

doi:10.1016/j.sbi.2014.02.004

Cited by 128 publications

(94 citation statements)

References 55 publications

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“…29–31 Computational studies are still mostly based on sub-microsecond simulations, or based on contact analysis or elastic network modeling of static crystal structures. 32 Notably, allosteric communication has been assumed to involve evolutionarily conserved 33 or positionally correlated 34 networks of residues. The complementarity of computational and experimental approaches, NMR spectroscopy in particular, in studying allostery can be easily appreciated.…”

Section: Introductionmentioning

confidence: 99%

Protein Allostery and Conformational Dynamics

2016

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The functions of many proteins are regulated through allostery, whereby effector binding at a distal site changes the functional activity (e.g., substrate binding affinity or catalytic efficiency) at the active site. Most allosteric studies have focused on thermodynamic properties, in particular, substrate binding affinity. Changes in substrate binding affinity by allosteric effectors have generally been thought to be mediated by conformational transitions of the proteins, or alternatively, by changes in the broadness of the free energy basin of the protein conformational state without shifting the basin minimum position. When effector binding changes the free energy landscape of a protein in conformational space, the change not only affects thermodynamic properties but also dynamic properties, including the amplitudes of motions on different timescales and rates of conformational transitions. Here we assess the roles of conformational dynamics in allosteric regulation. Two cases are highlighted where NMR spectroscopy and molecular dynamics simulation have been used as complementary approaches to identify residues possibly involved in allosteric communication. Perspectives on contentious issues, e.g., the relation between picosecond-nanosecond local and microsecond-millisecond conformational exchange dynamics, are presented.

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Section: Introductionmentioning

confidence: 99%

Protein Allostery and Conformational Dynamics

2016

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“…In recent years, computational studies have been found to be very useful in complementing experiments in elucidating allosteric mechanisms (Elber, 2011; Feher et al, 2014; Rousseau and Schymkowitz, 2005), including algorithms for identifying allosteric networks (Gerek and Ozkan, 2011; Ghosh and Vishveshwara, 2007; Kannan and Vishveshwara, 1999; Sethi et al, 2009; VanWart et al, 2014). In particular, molecular dynamics simulations have revealed two pathways and implicated a strong dynamic component in the allosteric regulation of thrombin by thrombomodulin (Gasper et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Two Pathways Mediate Interdomain Allosteric Regulation in Pin1

2015

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Summary Allostery is an essential means for regulating biomolecular functions and provides unique opportunities for drug design, yet our ability to elucidate allosteric mechanisms remains limited. Here, based on extensive molecular dynamics simulations, we present an atomistic picture of the pathways mediating the allosteric regulation of the PPIase domain of Pin1 by its WW domain. Two pathways jointly propagate the action of substrate-WW binding to produce closure and rigidification of three PPIase catalytic-site loops. One pathway preexists in the apo protein but remains dormant until substrate-WW binding completes the second. The reduction in conformational entropy and preorganization of the catalytic-site loops observed here may explain why substrate-WW binding enhances ligand affinity and catalytic activity of the PPIase domain, and suggest a combination drug therapy for Pin1-related diseases. Whereas the traditional view of allostery has emphasized conformational transition, our study uniquely identifies a distinct role of conformational dynamics in eliciting allostery.

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“…PDZ domain has been a classic model system to study single domain allostery without major structural changes (9,15,16) (Fig. 1A).…”

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Hidden electrostatic basis of dynamic allostery in a PDZ domain

Kumawat

Chakrabarty

2017

Proc. Natl. Acad. Sci. U.S.A.

138

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Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters. There is a significant population shift in the hydrogen-bonded network and salt bridges involving side chains on ligand binding. The ligand creates a local energetic perturbation that propagates in the form of dominolike changes in interresidue interaction pattern. There are significant changes in the nature of specific interactions (nonpolar/ polar) between interresidue contacts and accompanied side-chain reorientations that drive the major redistribution of energy. Interestingly, this internal redistribution and rewiring of side-chain interactions led to large cancellations resulting in small change in the overall enthalpy of the protein, thus making it difficult to detect experimentally. In contrast to the prevailing focus on the entropic or dynamic effects, we show that the internal redistribution and population shift in specific electrostatic interactions drive the allosteric modulation in the PDZ3 domain protein.A llosteric regulation of proteins plays a key role in physiological cell functions, biochemical and signal transduction pathways, and drug discovery (1-3). It has remained a challenge to understand how the thermodynamic perturbation caused by ligand binding at one site would propagate and modulate the structure and dynamics of distal regions of proteins. The prevailing models of structure-based allostery (4, 5) do not apply to the more recent examples of allostery without conformational change such as PDZ domain (6), CAP dimer (7), and met repressor (8). These examples have triggered the concept of dynamic allostery, where the side-chain dynamics is modulated on ligand binding and the origin has often been attributed to changes in the conformational entropy (9, 10). The modern view of allostery invokes a thermodynamic picture, where a population shift among preexisting conformational states occurs on binding the allosteric effector (11-13). It has also been suggested in the context of allostery without conformational change that "not observed does not imply that it is not there" (10) because crystallographic techniques may not resolve the relatively minor population shifts. An interesting idea has emerged that all proteins might be allosteric in nature (14).PDZ domain has been a classic model system to study single domain allostery without major structural changes (9, 15, 16) (Fig. 1A). PDZ domains are evolutionary conserved proteinprotein interaction module...

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Computational approaches to mapping allosteric pathways

Cited by 128 publications

References 55 publications

Protein Allostery and Conformational Dynamics

Protein Allostery and Conformational Dynamics

Two Pathways Mediate Interdomain Allosteric Regulation in Pin1

Hidden electrostatic basis of dynamic allostery in a PDZ domain

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