Mapping Allostery through Computational Glycine Scanning and Correlation Analysis of Residue–Residue Contacts

Johnson, Quentin R.; Lindsay, Richard J.; Nellas, Ricky B.; Fernandez, Elias J.; Shen, Tongye

doi:10.1021/bi501152d

Cited by 39 publications

(68 citation statements)

References 49 publications

(90 reference statements)

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“…After all, the nonbonded interactions are intimately coupled to the presence of contacts and their rearrangements. As a matter of fact, in the context of allosteric coupling it has been suggested that the residues that are in spatial proximity forming contacts are more likely to be coupled compared with the distal residues (37), and models have been proposed to construct a biophysical framework based on contacts acting as structural support for the propagation of information (41)(42)(43). We took a similar approach of identifying the possible differences in the side-chain contacts between the two end states by constructing the differential contact map (Materials and Methods) in Fig.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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“…Mining the time evolution data of 3N atomic coordinates (n = 2,505 atoms of CypA) for key features presents a "big data" problem. To simplify the complexity of the high-dimensional data, we established a data reduction scheme similar to the Computation of Allosteric Mechanism by Evaluating Residue-Residue Associations approach (35). The 3D Cartesian coordinates of the trajectory is condensed to a binary trajectory (consisting of 0s and 1s) of N res *(N res -1)/2 residue-residue contacts.…”

Section: Resultsmentioning

confidence: 99%

Dynamical network of residue–residue contacts reveals coupled allosteric effects in recognition, catalysis, and mutation

Doshi

Holliday

Eisenmesser

et al. 2016

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

152

186

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Detailed understanding of how conformational dynamics orchestrates function in allosteric regulation of recognition and catalysis remains ambiguous. Here, we simulate CypA using multiple-microsecond-long atomistic molecular dynamics in explicit solvent and carry out NMR experiments. We analyze a large amount of time-dependent multidimensional data with a coarse-grained approach and map key dynamical features within individual macrostates by defining dynamics in terms of residue-residue contacts. The effects of substrate binding are observed to be largely sensed at a location over 15 Å from the active site, implying its importance in allostery. Using NMR experiments, we confirm that a dynamic cluster of residues in this distal region is directly coupled to the active site. Furthermore, the dynamical network of interresidue contacts is found to be coupled and temporally dispersed, ranging over 4 to 5 orders of magnitude. Finally, using network centrality measures we demonstrate the changes in the communication network, connectivity, and influence of CypA residues upon substrate binding, mutation, and during catalysis. We identify key residues that potentially act as a bottleneck in the communication flow through the distinct regions in CypA and, therefore, as targets for future mutational studies. Mapping these dynamical features and the coupling of dynamics to function has crucial ramifications in understanding allosteric regulation in enzymes and proteins, in general.allostery | enzyme dynamics | residue-residue contacts | Cyclophilin A | molecular dynamics

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“…The values themselves are sensitive to m , and they have little direct meaning and should be mainly used for comparing the relative values. To connect the normalized values to the range of fluctuation of these contacts, one can look at eigenvalues and PC projections, such as Figure 4 of ref 36. We estimate the amplitude of (anti)cooperative ligand-binding motion expressed in Figure 4b for RXR:TR and RXR:CAR is a fluctuation of a few contact units.…”

Section: Resultsmentioning

confidence: 99%

“…These apo-approaching mutants used here are identical to those of RXR:TR complexes that we have studied previously. 36 As listed in Table S1 of the supporting information in ref 36, these 18 residues (V265, C269, A271, A272, Q275, L309, I310, F313, R316, A327, I345, F346, V349, C432, L433, H435, L436, F439) that constitute the binding pocket were selected by examining the crystal structure and representative snapshots of the wild-type RXR:TR. Through the simulations of these glycine mutants which have a weakened protein–ligand interaction, we can obtain a large ensemble of structures that are closer to the apo form ensemble.…”

Section: Systems and Methodsmentioning

confidence: 99%

The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor

Clark¹,

Wilder²,

Grayson³

et al. 2016

J. Phys. Chem. B

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The promiscuous protein retinoid X receptor (RXR) displays essential allosteric regulation of several members in the nuclear hormone receptor superfamily via heterodimerization and (anti)cooperative binding of cognate ligands. Here, the structural basis of the positive allostery of RXR and constitutive androstane receptor (CAR) is revealed. In contrast, a similar computational approach had previously revealed the mechanism for negative allostery in the complex of RXR and thyroid receptor (TR). By comparing the positive and negative allostery of RXR complexed with CAR and TR respectively, we reported the promiscuous allosteric control involving RXR. We characterize the allosteric mechanism by expressing the correlated dynamics of selected residue–residue contacts which was extracted from atomistic molecular dynamics simulation and statistical analysis. While the same set of residues in the binding pocket of RXR may initiate the residue–residue interaction network, RXR uses largely different sets of contacts (only about one-third identical) and allosteric modes to regulate TR and CAR. The promiscuity of RXR control may originate from multiple factors, including (1) the frustrated fit of cognate ligand 9c to the RXR binding pocket and (2) the different ligand-binding features of TR (loose) versus CAR (tight) to their corresponding cognate ligands.

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Mapping Allostery through Computational Glycine Scanning and Correlation Analysis of Residue–Residue Contacts

Cited by 39 publications

References 49 publications

Hidden electrostatic basis of dynamic allostery in a PDZ domain

Hidden electrostatic basis of dynamic allostery in a PDZ domain

Dynamical network of residue–residue contacts reveals coupled allosteric effects in recognition, catalysis, and mutation

The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor

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