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(2013). Systems Biology.
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Aalten, V. D. M. F., Groot, D. B. L., Findlay, J. B. C., Berendsen, H. J. C., & Amadei, A. (1997). A comparison of techniques for calculating protein essential dynamics. J. Comput. Chem., 18(2), 169–181.
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Abad-Zapatero, C., Griffith, J. P., Sussman, J. L., & Rossmann, M. G. (1987). Refined crystal structure of dogfish M4 apo-lactate dehydrogenase. J. Mol. Biol., 198(3), 445–467.
Abstract: The crystal structure of M4 apo-lactate dehydrogenase from the spiny dogfish (Squalus acanthius) was initially refined by a constrained-restrained, and subsequently restrained, least-squares technique. The final structure contained 286 water molecules and two sulfate ions per subunit and gave an R-factor of 0.202 for difraction data between 8.0 and 2.0 A resolution. The upper limit for the co-ordinate accuracy of the atoms was estimated to be 0.25 A. The elements of secondary structure of the refined protein have not changed from those described previously, except for the appearance of a one-and-a-half turn 3(10) helix immediately after beta J. There is also a short segment of 3(10) helix between beta C and beta D in the part of the chain that connects the two beta alpha beta alpha beta units of the six-stranded parallel sheet (residues Tyr83 to Ala87). Examination of the interactions among the different elements of secondary structure by means of a surface accessibility algorithm supports the four structural clusters in the subunit. The first of the two sulfate ions is in the active site and occupies a cavity near the essential His195. Its nearest protein ligands are Arg171, Asp168 and Asn140. The second sulfate ion is located near the P-axis subunit interface. It is liganded by His188 and Arg173. These two residues are conserved in bacterial lactate dehydrogenase and form part of the fructose 1,6-bisphosphate effector binding site. Two other data sets in which one (collected at pH 7.8) or both (collected at pH 6.0) sulfate ions were replaced by citrate ions were also analyzed. Five cycles of refinement with respect to the pH 6.0 data (25 to 2.8 A resolution) resulted in an R value of 0.191. Only water molecules occupy the subunit boundary anion binding site at pH 7.8. The amino acid sequence was found to be in poor agreement with (2Fobs-Fcalc) electron density maps for the peptide between residues 207 and 211. The original sequence WNALKE was replaced by NVASIK. The essential His195 is hydrogen bonded to Asp168 on one side and Asn140 on the other. The latter residue is part of a turn that contains the only cis peptide bond of the structure at Pro141. The “flexible loop” (residues 97 to 123), which folds down over the active center in ternary complexes of the enzyme with substrate and coenzyme, has a well-defined structure. Analysis of the environment of Tyr237 suggests how its chemical modification inhibits the enzyme.
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Abraham, M. J., Murtola, T., Schulz, R., P\’all, S. \’ard, Smith, J. C., Hess, B., et al. (2015). GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 1, 19–25.
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Acmg. (2000). ACMG recommendations for standards for interpretation of sequence variations. Genetics in Medicine, 2(5), 302–303.
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Adamczyk, A. J., Cao, J., Kamerlin, S. C., & Warshel, A. (2011). Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions. Proc Natl Acad Sci U S A, 108(34), 14115–14120.
Abstract: The proposal that enzymatic catalysis is due to conformational fluctuations has been previously promoted by means of indirect considerations. However, recent works have focused on cases where the relevant motions have components toward distinct conformational regions, whose population could be manipulated by mutations. In particular, a recent work has claimed to provide direct experimental evidence for a dynamical contribution to catalysis in dihydrofolate reductase, where blocking a relevant conformational coordinate was related to the suppression of the motion toward the occluded conformation. The present work utilizes computer simulations to elucidate the true molecular basis for the experimentally observed effect. We start by reproducing the trend in the measured change in catalysis upon mutations (which was assumed to arise as a result of a “dynamical knockout” caused by the mutations). This analysis is performed by calculating the change in the corresponding activation barriers without the need to invoke dynamical effects. We then generate the catalytic landscape of the enzyme and demonstrate that motions in the conformational space do not help drive catalysis. We also discuss the role of flexibility and conformational dynamics in catalysis, once again demonstrating that their role is negligible and that the largest contribution to catalysis arises from electrostatic preorganization. Finally, we point out that the changes in the reaction potential surface modify the reorganization free energy (which includes entropic effects), and such changes in the surface also alter the corresponding motion. However, this motion is never the reason for catalysis, but rather simply a reflection of the shape of the reaction potential surface.
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Adamic, L. A., Lukose, R. M., Puniyani, A. R., & Huberman, B. A. (2001). Search in power-law networks. Physical Review E, 64(4), 046135.
Abstract: Many communication and social networks have power-law link distributions, containing a few nodes that have a very high degree and many with low degree. The high connectivity nodes play the important role of hubs in communication and networking, a fact that can be exploited when designing efficient search algo- rithms. We introduce a number of local search strategies that utilize high degree nodes in power-law graphs and that have costs scaling sublinearly with the size of the graph. We also demonstrate the utility of these strategies on the GNUTELLA peer-to-peer network.
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Adams, M. J., Buehner, M., Chandrasekhar, K., Ford, G. C., Hackert, M. L., Liljas, A., et al. (1973). Structure-function relationships in lactate dehydrogenase. Proc Natl Acad Sci U S A, 70(7), 1968–1972.
Abstract: The binding of coenzyme and substrate are considered in relation to the known primary and tertiary structure of lactate dehydrogenase (EC 1.1.1.27). The adenine binds in a hydrophobic crevice, and the two coenzyme phosphates are oriented by interactions with the protein. The positively charged guanidinium group of arginine 101 then folds over the negatively charged phosphates, collapsing the loop region over the active center and positioning the unreactive B side of the nicotinamide in a hydrophobic protein environment. Collapse of the loop also introduces various charged groups into the vicinity of the substrate binding site. The substrate is situated between histidine 195 and the C4 position on the nicotinamide ring, and is partially oriented by interactions between its carboxyl group and arginine 171. The spatial arrangements of these groups may provide the specificity for the L-isomer of lactate.
Keywords: Amino Acid Sequence Animals Binding Sites Crystallography L-Lactate Dehydrogenase L-Lactate Dehydrogenase: metabolism Models Molecular Conformation NAD NAD: metabolism NADP NADP: metabolism Sharks Structural Structure-Activity Relationship
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Adler, M., Mayo, A., Zhou, X., Franklin, R. A., Jacox, J. B., Medzhitov, R., et al. (2018). Endocytosis as a stabilizing mechanism for tissue homeostasis. Proc. Natl. Acad. Sci. U.S.A., , 201714377.
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Agarwal, P. K., Geist, A., & Gorin, A. (2004). Protein Dynamics and Enzymatic Catalysis: Investigating the Peptidyl−Prolyl Cis−Trans Isomerization Activity of Cyclophilin A†. Biochemistry, 43(33), 10605–10618.
Abstract: A growing body of evidence suggests a connection between protein dynamics and enzymatic catalysis. In this paper, we present a variety of computational studies designed to investigate the role of protein dynamics in the detailed mechanism of peptidyl-prolyl cis-trans isomerization catalyzed by human cyclophilin A. The results identify a network of protein vibrations, extending from surface regions of the enzyme to the active site and coupled to substrate turnover. Indications are that this network may have a role in promoting catalysis. Crucial parts of this network are found to be conserved in 10 cyclophilin structures from six different species. Experimental evidence for the existence of this network comes from previous NMR relaxation studies, where motions in several residues, forming parts of this network, were detected only during substrate turnover. The high temperature factors (from X-ray crystal structures) associated with the network residues provide further evidence of these vibrations. Along with the knowledge of enzyme structure, this type of network could provide new insights into enzymatic catalysis and the effect of distant ligand binding on protein function. The procedure outlined in this paper is general and can be applied to other enzymatic systems as well. This presents an interesting opportunity; collaborative experimental and theoretical investigations designed to characterize in detail the nature and function of this type of network could enhance the understanding of protein dynamics in enzymatic catalysis.
Keywords: Amino Acid Sequence Binding Sites Catalysis Computer Simulation Conserved Sequence Cyclophilin A Cyclophilin A: chemistry Cyclophilin A: metabolism Humans Isomerism Motion Peptidylprolyl Isomerase Peptidylprolyl Isomerase: chemistry Peptidylprolyl Isomerase: metabolism Thermodynamics Vibration
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