Energy exchange network of inter-residue interactions within a thermally fluctuating protein molecule: A computational study

Ishikura, Takakazu; Iwata, Yuji; Hatano, Tatsuro; Yamato, Takahisa

doi:10.1002/jcc.23989

Cited by 41 publications

(87 citation statements)

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“…On the other hand, the dynamic process of allosteric communication itself, also referred to as "allosteric transition" between the free and bound end states, has been rarely investigated (15)(16)(17)(18)(19); this is because of the experimental challenge of observing transition pathways and the timescale limitations of molecular dynamics simulations. Nonetheless, a number of theoretical models have been proposed that aim to predict the pathways of the intramolecular signal propagation (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Compared with other biomolecular processes such as protein folding (33), however, it seems fair to say that the dynamical evolution of allosteric transitions is still not well understood.…”

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confidence: 99%

Time-resolved observation of protein allosteric communication

Buchenberg

Sittel

Stock

2017

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

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Allostery represents a fundamental mechanism of biological regulation that is mediated via long-range communication between distant protein sites. Although little is known about the underlying dynamical process, recent time-resolved infrared spectroscopy experiments on a photoswitchable PDZ domain (PDZ2S) have indicated that the allosteric transition occurs on multiple timescales. Here, using extensive nonequilibrium molecular dynamics simulations, a time-dependent picture of the allosteric communication in PDZ2S is developed. The simulations reveal that allostery amounts to the propagation of structural and dynamical changes that are genuinely nonlinear and can occur in a nonlocal fashion. A dynamic network model is constructed that illustrates the hierarchy and exceeding structural heterogeneity of the process. In compelling agreement with experiment, three physically distinct phases of the time evolution are identified, describing elastic response ([Formula: see text] ns), inelastic reorganization ([Formula: see text] ns), and structural relaxation ([Formula: see text]s). Issues such as the similarity to downhill folding as well as the interpretation of allosteric pathways are discussed.

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confidence: 99%

Time-resolved observation of protein allosteric communication

Buchenberg

Sittel

Stock

2017

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

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“…in proteins. Recently, we introduced a concept of Energy Exchange Network (EEN) such that it represents the network of nodes (= amino acid residues) whose connectivity is defined based on the irEC values of residue pairs, and examined the molecular mechanism of hidden dynamic allostery of a small globular protein, PDZ3 18,95,170. Some of these examples are explained in the next section.…”

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confidence: 99%

Mapping Energy Transport Networks in Proteins

Leitner

Yamato

2018

Reviews in Computational Chemistry

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INTRODUCTIONThe response of proteins to chemical reactions or impulsive excitation that occurs within the molecule has fascinated chemists for decades. [1][2][3] In recent years ultrafast X-ray studies have provided ever more detailed information about the evolution of protein structural change following ligand photolysis, 4-5 and time-resolved IR and Raman techniques, e.g., have provided detailed pictures of the nature and rate of energy transport in peptides and proteins, [6][7][8][9][10][11] including recent advances in identifying transport through individual amino acids of several heme proteins. [12][13][14] Computational tools to locate energy transport pathways in proteins have also been advancing. 15 Energy transport pathways in proteins have since some time been identified by molecular dynamics (MD) simulations, [16][17] and more recent efforts have focused on the development of coarse graining approaches, 18-29 some of which have exploited analogies to thermal transport in other molecular materials. [30][31][32][33][34][35] With the identification of pathways in proteins and protein 2 complexes, network analysis has been applied to locate residues that control protein dynamics and possibly allostery, [36][37][38] where chemical reactions at one binding site mediate reactions at distance sites of the protein. In this chapter we review approaches for locating computationally energy transport networks in proteins. We present background into energy and thermal transport in condensed phase and macromolecules that underlies the approaches we discuss before turning to a description of the approaches themselves. We also illustrate the application of the computational methods for locating energy transport networks and simulating energy dynamics in proteins with several examples.One of the themes that we address in this chapter is the difference between energy transport in condensed phase generally and in a folded polymer such as a protein specifically. While the approaches that we present and detail are based on linearresponse theory for transport, we apply them to a system, a protein, where energy transport occurs highly anisotropically.We are mainly concerned with the characterization of such anisotropic transport, not simply the calculation of transport coefficients for a particular object, though that information can also be calculated starting with the approaches we present. The focus here then is on local energy transport coefficients, such as local energy conductivities and diffusivities, as discussed below, and how these local transport properties connect into a network that mediates energy dynamics in the protein. It is the network of such local energy transport coefficients that, once identified and located, can be used to model the global energy dynamics in a protein, as we describe.That energy transport pathways exist, i.e., energy does not simply flow isotropically through a globular protein, is an inherent property of the geometry of a 3 folded protein, [62][63][64][65][66][67][68][69][70] which i...

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“…Karplus and coworkers have revealed two continuous correlation pathways in a PDZ2 domain and highlighted the existence of such pathways even in the absence of the ligand (24). A number of theoretical (23,26,27) and experimental (6, 28) studies propose multiple allosteric pathways for PDZ domains on the basis of evolutionary information (29, 30), local structural changes (22, 31, 32), heat-diffusion pathways (33, 34), and energy connectivity networks (35,36). Most of the existing approaches look for Significance Allosteric regulation is a crucial component in biochemical pathways, where ligand binding to an allosteric site modulates the enzymatic activity at a distant functional site.…”

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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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Energy exchange network of inter-residue interactions within a thermally fluctuating protein molecule: A computational study

Cited by 41 publications

References 47 publications

Time-resolved observation of protein allosteric communication

Time-resolved observation of protein allosteric communication

Mapping Energy Transport Networks in Proteins

Hidden electrostatic basis of dynamic allostery in a PDZ domain

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