Pump‐probe molecular dynamics as a tool for studying protein motion and long range coupling

Sharp, Kim A.; Skinner, John J.

doi:10.1002/prot.21146

Cited by 96 publications

(135 citation statements)

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“…To obtain the missing bond parameters for the sulfonate groups, the antechamber tool was employed. 60 The side chains of all four histidine residues (33,54,72, and 87) of PDZ2S were chosen electrostatically neutral (mono-protonated). The lengths of bonds involving hydrogens were constrained, 61 allowing for a 2 fs time step.…”

Section: Methods Simulation Set-upmentioning

confidence: 99%

“…16 The nature of the subsequent ligand-induced intramolecular signaling process, however, remains a matter of debate, although various proposals of signaling pathways exist. [30][31][32][33][34][35][36][37][38] To facilitate a dynamic perspective of the allosteric mechanism, recently Buchli et al 45 presented a time-resolved study of the transition from the free to the bound state of PDZ2 triggered by a molecular photoswitch. [46][47][48][49][50][51] By covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that affects the cis → trans photoisomerization of azobenzene, they were able to initiate a conformational change similar to the free-bound transition.…”

Section: Introductionmentioning

confidence: 99%

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Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

et al. 2014

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A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligandbound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and the trans state of the photoswitch, in explicit water. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes, that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein. October 9, 2014 * To whom correspondence should be addressed 1 Abstract A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligandbound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and the trans state of the photoswitch, in explicit water. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes, that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein.

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Section: Methods Simulation Set-upmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

et al. 2014

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“…By clustering the binding induced fluctuation profiles of a diverse set of PDZ domains, we showed that ENM predicted normal modes not only can identify the structural regions and types of correlated fluctuations critical for binding of Class I and Class II peptides but also predicts binding selectivity of PDZs. 49 The challenge of PDZ domain (i.e., the reasons behind their selectivity and promiscuity) and their link to many different diseases has led to a number of important experimental 50,51 and computational 49,[52][53][54][55][56][57][58] studies. Niv and Weinstein also developed a flexible docking scheme (called PDZDocScheme), 56 which is based on simulated annealing molecular dynamics with the soft core potential or flexible binding site side chains, followed by rotamer optimization.…”

Section: Introductionmentioning

confidence: 99%

A flexible docking scheme to explore the binding selectivity of PDZ domains

Gerek

Ozkan

2010

Protein Science

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Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å . We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

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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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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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Pump‐probe molecular dynamics as a tool for studying protein motion and long range coupling

Cited by 96 publications

References 74 publications

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

A flexible docking scheme to explore the binding selectivity of PDZ domains

Hidden electrostatic basis of dynamic allostery in a PDZ domain

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