Comparison of the dynamics of bovine and human angiogenin: a molecular dynamics study

Madhusudhan, M.S.; Vishveshwara, Saraswathi

doi:10.1002/(sici)1097-0282(199902)49:2<131::aid-bip3>3.0.co;2-w

Cited by 6 publications

(6 citation statements)

References 36 publications

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“…On the other hand, His 114 and Asp 116 exhibit a significant conformational freedom. This behavior derived from previous experimental17, 41, 43 and molecular dynamics22, 23 studies is in line with the results of the present analysis (data not shown).…”

Section: Resultssupporting

confidence: 93%

“…The low angiogenin ribonucleotidic activity, which is 10 5 times lower than RNase A, has been attributed to this steric hindrance 17, 19, 27, 43. Although these hydrogen bonds were reported to be well retained during the whole length of a 1‐ns MD simulation,22 they are frequently broken in the present MD simulations (Fig. 4).…”

Section: Resultsmentioning

confidence: 65%

“…To this end, using molecular dynamics (MD) simulations and essential dynamics (ED) analysis, we have compared the collective motions of Ang to those of RNase A (sequence identity 33%). It is worth mentioning that MD studies previously performed on Ang were essentially focused on active‐site residue motions22 and on the role that water molecules play in angiogenin23 and did not consider the occurrence of concerted subdomain motions.…”

Section: Introductionmentioning

confidence: 99%

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Subtle functional collective motions in pancreatic‐like ribonucleases: From ribonuclease A to angiogenin

Merlino

Vitagliano

Ceruso³

et al. 2003

Proteins

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The analysis of the dynamic behavior of enzymes is fundamental to structural biology. A direct relationship between protein flexibility and biological function has been shown for bovine pancreatic ribonuclease (RNase A) (Rasmussen et al., Nature 1992;357:423-424). More recently, crystallographic studies have shown that functional motions in RNase A involve the enzyme beta-sheet regions that move concertedly on substrate binding and release (Vitagliano et al., Proteins 2002;46:97-104). These motions have been shown to correspond to intrinsic dynamic properties of the native enzyme by molecular dynamics (MD) simulations. To unveil the occurrence of these collective motions in other members of pancreatic-like superfamily, we carried out MD simulations on human angiogenin (Ang). Essential dynamics (ED) analyses performed on the trajectories reveal that Ang exhibits collective motions similar to RNase A, despite the limited sequence identity (33%) of the two proteins. Furthermore, we show that these collective motions are also present in ensembles of experimentally determined structures of both Ang and RNase A. Finally, these subtle concerted beta-sheet motions were also observed for other two members of the pancreatic-like superfamily by comparing the ligand-bound and ligand-free structures of these enzymes. Taken together, these findings suggest that pancreatic-like ribonucleases share an evolutionary conserved dynamic behavior consisting of subtle beta-sheet motions, which are essential for substrate binding and release.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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Subtle functional collective motions in pancreatic‐like ribonucleases: From ribonuclease A to angiogenin

Merlino

Vitagliano

Ceruso³

et al. 2003

Proteins

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“…The CpA RMSD trajectory is shown in thick line and the UpG trajectory in thin. The trajectory of the native angiogenin18 is shown as a dotted line.…”

Section: Resultsmentioning

confidence: 99%

Computer modeling and molecular dynamics simulations of ligand bound complexes of bovine angiogenin: Dinucleotide topology at the active site of RNase a family proteins

2001

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We have undertaken the modeling of substrate-bound structures of angiogenin. In our recent study, we modeled the dinucleotide ligand binding to human angiogenin. In the present study, the substrates CpG, UpG, and CpA were docked onto bovine angiogenin. This was achieved by overcoming the problem of an obstruction to the B1 site by the C-terminus and identifying residues that bind to the second base. The modeled complexes retain biochemically important interactions. The docked models were subjected to 1 ns of molecular dynamics, and structures from the simulation were refined by using simulated annealing. Our models explained the enzyme's specificity for both B1 and B2 bases as observed experimentally. The nature of binding of the dinucleotide substrate was compared with that of the mononucleotide product. The models of these complexes were also compared with those obtained earlier with human angiogenin. On the basis of the simulations and annealed structures, we came up with a consensus topology of dinucleotide ligands that binds to human and bovine angiogenins. This dinucleotide conformation can serve as a starting model for ligand-bound complex structures for RNase A family of proteins. We demonstrated this capability by generating the complex structure of CpA bound to eosinophilderived neurotoxin (EDN) by fitting the consensus topology of CpA to the crystal structure of native EDN. Proteins 2001;45:30 -39.

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“…However, only a restricted set have been subjected to dynamic investigation, considerably restricting flexibility comparisons between evolutionarily diverse enzymes with this structural fold. Although this is not an entirely comprehensive list, experimental and/or theoretical dynamic studies have been performed on free, ligand‐bound, wild‐type and/or mutant forms of human and rat RNase 1 , human eosinophil‐derived neurotoxin (EDN, or RNase 2) , human ECP (or RNase 3) , human RNase 4 , bovine and human angiogenin (hANG, RNase 5) , the northern leopard frog ranpirnase (Onconase) , and monomeric derivatives of bovine seminal RNase (BS‐RNase) . The details of some of these dynamic studies will now be briefly described and compared with the local and global motional behavior of RNase A.…”

Section: Conserved Functional Motions Among Structural Homologsmentioning

confidence: 99%

Structural and functional importance of local and global conformational fluctuations in the RNase A superfamily

Gagné

Doucet

2013

The FEBS Journal

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Understanding the relationship between protein structure and flexibility is of utmost importance for deciphering the tremendous rates of reactions catalyzed by enzyme biocatalysts. It has been postulated that protein homologs have evolved similar dynamic fluctuations to promote catalytic function, a property that would presumably be encoded in their structural fold. Using one of the best-characterized enzyme systems of the past century, we explore this hypothesis by comparing the numerous and diverse flexibility reports available for a number of structural and functional homologs of the pancreatic-like RNase A superfamily. Using examples from the literature and from our own work, we cover recent and historical evidence pertaining to the highly dynamic nature of this important structural fold, as well as the presumed importance of local and global concerted motions on the ribonucleolytic function. This minireview does not pretend to cover the overwhelming RNase A literature in a comprehensive manner; rather, efforts have been made to focus on the characterization of multiple timescale motions observed in the free and/or ligand-bound structural homologs as they proceed along the reaction coordinates. Although each characterized enzyme of this architectural fold shows unique motional features on a local scale, accumulating evidence from X-ray crystallography, NMR spectroscopy and molecular dynamics simulations suggests that global dynamic fluctuations, such as the functionally relevant hinge-bending motion observed in the prototypical RNase A, are shared between homologs of the pancreatic-like RNase superfamily. These observations support the hypothesis that analogous dynamic residue clusters are evolutionarily conserved among structural and functional homologs catalyzing similar enzymatic reactions.

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Comparison of the dynamics of bovine and human angiogenin: a molecular dynamics study

Cited by 6 publications

References 36 publications

Subtle functional collective motions in pancreatic‐like ribonucleases: From ribonuclease A to angiogenin

Subtle functional collective motions in pancreatic‐like ribonucleases: From ribonuclease A to angiogenin

Computer modeling and molecular dynamics simulations of ligand bound complexes of bovine angiogenin: Dinucleotide topology at the active site of RNase a family proteins

Structural and functional importance of local and global conformational fluctuations in the RNase A superfamily

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