Communication maps computed for homodimeric hemoglobin: Computational study of water-mediated energy transport in proteins

Gnanasekaran, Ramachandran; Agbo, Johnson K.; Leitner, David M.

doi:10.1063/1.3623423

Cited by 55 publications

(99 citation statements)

References 65 publications

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“…Yet, it is still an open question as for how proteins, say enzymes, exploit the vibrational excitations through the signal propagation to regulate catalysis of chemical reactions. In the past decade or two, growing number of theoretical methods were proposed to elucidate intramolecular signal propagation pathways (39)(40)(41)(42)(43)(44)(45)(46)(47)(48). In general, the methods can be divided into two categoriesstructural/dynamical equilibrium approaches (42-44, 46, 47) and those of non-equilibrium (39-41, 45, 48, 49).…”

Section: Introductionmentioning

confidence: 99%

“…Although the "mutual correlated residues" were identified by PPMD, the time order of signal propagation is absent. Leitner's group combines the non-equilibrium MD and the normal mode relaxation process to study the diffusivity of heat current in the homodimeric hemoglobin (39). Given an initial position and velocity, the normal mode relaxation method provides the displacement and velocity as a function of time, which serves as the route to estimate the kinetic energy propagation.…”

Section: Introductionmentioning

confidence: 99%

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Intramolecular Communication and Allosteric Sites in Enzymes Unraveled by Time-Dependent Linear Response Theory

Huang

Chang-Chein

Yang

2019

Preprint

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It has been an established idea in recent years that protein is a physiochemically connected network. Allostery, understood in this new context, is a manifestation of residue communicating to remote parts in a molecule, and hence a rising interest to identify communication pathways within such a network. Recently, we have developed the timedependent linear response theories (td-LRTs), which shown to well interpret the ligand photodissociation relaxation dynamics of myoglobin. In this article, we applied the td-LRT with impulse force to investigate the allostery on an enzyme system -the dihydrofolate reductase (DHFR), which catalyze the hydride transfer (HT) reaction -the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) using the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). We developed a connection matrix to record the counts of mechanical signals propagating through donor-acceptor pairs launched from the active sites with the td-LRT. Through the connection matrix, the communication score (CS) of each residue is assigned, which quantify how often the signals propagate through a residue in its most accessible way. The sites with high CS are termed "intramolecular communication centers (ICCs)", which were shown to be highly conservative. Furthermore, we showed that the HT rate reduction by a single residue mutation is highly correlated with its CS. Especially, the mysterious 200-fold HT rate reduction of the distal mutation G121V from kinetic isotope effect experiment is well described by our model with its ultra-high CS which means the G121 participating on the signal propagation process most frequently. On the other hand, several mutants: G67V, S148A and W133F causing minor HT rate reduction were described by its low CS, which means fewer signals through those sites. We proposed that the fold of HT rate reduction for a given mutant is an exponential function of its CS, which suggests that the dynamics signal propagation in the wild type play a background role to facilitate the HT quantitatively.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intramolecular Communication and Allosteric Sites in Enzymes Unraveled by Time-Dependent Linear Response Theory

Huang

Chang-Chein

Yang

2019

Preprint

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“…Coupling of protein and water dynamics, for example, has been examined by molecular simulations [1][2][3][4][5][6][7][8][9][10] and a growing number of experimental probes [11][12][13][14], and a wide variety of dynamical time scales have been found [15,16] due to the heterogeneity of protein-water interactions. One class of proteins for which protein-water interactions are critical to function is antifreeze proteins (AFPs).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Water and Hydrogen Bond Dynamics at the Surface of an Antifreeze Protein

Gnanasekaran

Leitner

2012

Journal of Atomic, Molecular, and Optical Physics

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We examine dynamics of water molecules and hydrogen bonds at the water-protein interface of the wild-type antifreeze protein from spruce budworm Choristoneura fumiferana and a mutant that is not antifreeze active by all-atom molecular dynamics simulations. Water dynamics in the hydration layer around the protein is analyzed by calculation of velocity autocorrelation functions and their power spectra, and hydrogen bond time correlation functions are calculated for hydrogen bonds between water molecules and the protein. Both water and hydrogen bond dynamics from subpicosecond to hundred picosecond time scales are sensitive to location on the protein surface and appear correlated with protein function. In particular, hydrogen bond lifetimes are longest for water molecules hydrogen bonded to the ice-binding plane of the wild type, whereas hydrogen bond lifetimes between water and protein atoms on all three planes are similar for the mutant.

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“…In contrast, allosteric pathways aim to describe routes through which excitations propagate across a protein91819. Recent experimental2021 and computational22232425 work has showcased the anisotropy of energy flow in globular proteins, and linked anisotropy and allosteric behaviour2125, for example, the anisotropic internal energy flow in albumin is altered by the binding of an allosteric ligand21. Our graph-theoretical calculations also reveal the anisotropy of the internal propagation of perturbations in proteins.…”

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confidence: 77%

Prediction of allosteric sites and mediating interactions through bond-to-bond propensities

2016

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Allostery is a fundamental mechanism of biological regulation, in which binding of a molecule at a distant location affects the active site of a protein. Allosteric sites provide targets to fine-tune protein activity, yet we lack computational methodologies to predict them. Here we present an efficient graph-theoretical framework to reveal allosteric interactions (atoms and communication pathways strongly coupled to the active site) without a priori information of their location. Using an atomistic graph with energy-weighted covalent and weak bonds, we define a bond-to-bond propensity quantifying the non-local effect of instantaneous bond fluctuations propagating through the protein. Significant interactions are then identified using quantile regression. We exemplify our method with three biologically important proteins: caspase-1, CheY, and h-Ras, correctly predicting key allosteric interactions, whose significance is additionally confirmed against a reference set of 100 proteins. The almost-linear scaling of our method renders it suitable for high-throughput searches for candidate allosteric sites.

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Communication maps computed for homodimeric hemoglobin: Computational study of water-mediated energy transport in proteins

Cited by 55 publications

References 65 publications

Intramolecular Communication and Allosteric Sites in Enzymes Unraveled by Time-Dependent Linear Response Theory

Intramolecular Communication and Allosteric Sites in Enzymes Unraveled by Time-Dependent Linear Response Theory

Analysis of Water and Hydrogen Bond Dynamics at the Surface of an Antifreeze Protein

Prediction of allosteric sites and mediating interactions through bond-to-bond propensities

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