Molecular modeling and dynamics studies of cytidylate kinase from Mycobacterium tuberculosis H37Rv

Caceres, Rafael Andrade; Timmers, Luís Fernando Saraiva Macedo; Vivan, A; Schneider, Cristopher Z.; Basso, Luiz Augusto; Azevedo, Walter Filgueira de; Santos, Daniel Silas Veras dos

doi:10.1007/s00894-008-0291-2

Cited by 16 publications

(12 citation statements)

References 33 publications

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“…The computed free energy for a number of PDB ligand-receptor complexes was studied and compared with experimental binding affinity. A substantial degree of correlation between the computed free energy and experimental binding affinity was found, which suggests that PEARLS may be useful in facilitating the energetic analysis of ligand-protein, ligand-nucleic acid, and protein-nucleic acid interactions (Han et al, 2006;Sperandio et al, 2006;Ghosh et al, 2007;Vijjulatha and Kanth, 2007;Maity et al, 2008;Caceres et al, 2008;Pauli et al, 2008).…”

Section: Calculation Of Ligand-protein Interaction Energymentioning

confidence: 91%

Binding dynamics and energetic insight into the molecular forces driving nucleotide binding by guanylate kinase

Kandeel

Kitade

2010

J of Molecular Recognition

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Plasmodium deoxyguanylate pathways are an attractive area of investigation for future metabolic and drug discovery studies due to their unique substrate specificities. We investigated the energetic contribution to guanylate kinase substrate binding and the forces underlying ligand recognition. In the range from 20 to 35°C, the thermodynamic profiles displayed marked decrease in binding enthalpy, while the free energy of binding showed little changes. GMP produced a large binding heat capacity change of -356 cal mol(-1) K(-1), indicating considerable conformational changes upon ligand binding. Interestingly, the calculated ΔCp was -32 cal mol(-1) K(-1), indicating that the accessible surface area is not the central change in substrate binding, and that other entropic forces, including conformational changes, are more predominant. The thermodynamic signature for GMP is inconsistent with rigid-body association, while dGMP showed more or less rigid-body association. These binding profiles explain the poor catalytic efficiency and low affinity for dGMP compared with GMP. At low temperature, the ligands bind to the receptor site under the effect of hydrophobic forces. Interestingly, by increasing the temperature, the entropic forces gradually vanish and proceed to a nonfavorable contribution, and the interaction occurs mainly through bonding, electrostatic forces, and van der Waals interactions.

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Section: Calculation Of Ligand-protein Interaction Energymentioning

confidence: 91%

Binding dynamics and energetic insight into the molecular forces driving nucleotide binding by guanylate kinase

Kandeel

Kitade

2010

J of Molecular Recognition

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“…6). The larger specificity constant of E. coli CMK for CMP (2.9 Â 10 6 M À1 s À1 ) [13] as compared to MtCMK (0.4 Â 10 6 M À1 s À1 ) [11] is consistent with increased intermolecular contacts in the former [37]. The amino acids of E. coli that form H-bonds to cytosine (Asp132, Arg110 and Arg188), which correspond to Asp134, Arg111 and Arg190 in MtCMK (Fig.…”

Section: Sequence Alignment and Mtcmk Structural Analysismentioning

confidence: 60%

“…The unfavorable entropic contribution for CMP binding process is likely due to large motions of NMP domain that occurs on MtCMK: CMP binary complex formation [37]. The larger unfavorable entropy for CDP may indicate protein conformational changes that restrict the protein to a particular conformer to facilitate product release from MtCMK: CDP binary complex to yield free enzyme, which is compensated for by the larger enthalpic contribution probably due to an extra phosphoryl group of CDP as compared to CMP.…”

Section: Thermodynamic Signatures Of Substrate(s) and Product(s) Intementioning

confidence: 98%

“…The crystallographic structures of E. coli CMP kinase (Protein Data Bank accession numbers: 1KDO, 1KDP, 1KDR, 1CKE, and 2CMK) [13,18] in complex with substrates or products together with a three-dimensional model of MtCMK in complex with CMP [37], Fig. 7 permit to propose the possible amino acid side chains in MtCMK that are involved in binding of the phosphoryl group acceptors (CMP, dCMP, AraCMP, ddCMP).…”

Section: Sequence Alignment and Mtcmk Structural Analysismentioning

confidence: 99%

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Kinetic mechanism and energetics of binding of phosphoryl group acceptors to Mycobacterium tuberculosis cytidine monophosphate kinase

Jaskulski

Rosado

Rostirolla

et al. 2013

Archives of Biochemistry and Biophysics

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Cytidine monophosphate kinase from Mycobacterium tuberculosis (MtCMK) likely plays a role in supplying precursors for nucleic acid synthesis. MtCMK catalyzes the ATP-dependent phosphoryl group transfer preferentially to CMP and dCMP. Initial velocity studies and Isothermal titration calorimetry (ITC) measurements showed that MtCMK follows a random-order mechanism of substrate (CMP and ATP) binding, and an ordered mechanism for product release, in which ADP is released first followed by CDP. The thermodynamic signatures of CMP and CDP binding to MtCMK showed favorable enthalpy and unfavorable entropy, and ATP binding was characterized by favorable changes in enthalpy and entropy. The contribution of linked protonation events to the energetics of MtCMK:phosphoryl group acceptor binary complex formation suggested a net gain of protons. Values for the pKa of a likely chemical group involved in proton exchange and for the intrinsic binding enthalpy were calculated. The Asp187 side chain of MtCMK is suggested as the likely candidate for the protonation event. Data on thermodynamics of binary complex formation were collected to evaluate the contribution of 2'-OH group to intermolecular interactions. The data are discussed in light of functional and structural comparisons between CMP/dCMP kinases and UMP/CMP ones.

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“…The sequence analysis result based on BLASTp, there were 220 amino acids only 88 amino acids had been matched. A total 1000 models had been generated for each binary complex and the final model selected based on MODELLER objective function [21]…”

Section: Resultsmentioning

confidence: 99%

Insight from the structural molecular model of cytidylate kinase from Mycobacterium tuberculosis

Verma

Singh

2013

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Mycobacterium tuberculosis is a gram-positive bacterium causes tuberculosis in human. H37Rv strain is a pathogenic strain utilized for tuberculosis research. The cytidylate mono-phosphate (CMP) kinase of Mycobacterium tuberculosis belongs to the family nucleoside mono-phosphate kinase (NMK), this enzyme is required for the bacterial growth. Therefore, it is important to study the structural and functional features of this enzyme in the control of the disease. Hence, we developed the structural molecular model of the CMP kinase protein from Mycobacterium tuberculosis by homology modeling using the software MODELLER (9v10). Based on sequence similarity with protein of known structure (template) of Mycobacterium smegmatis (PDB ID: 3R20) was chosen from protein databank (PDB) by using BLASTp. The energy of constructed models was minimized and the qualities of the models were evaluated by PROCHECK and VERRIFY-3D. Resulted Ramachandran plot analysis showed that conformations for 100.00% of amino acids residues are within the most favored regions. A possible homologous deep cleft active site was identified in the Model using CASTp program. Amino acid composition and polarity of that protein was observed by CLC-Protein Workbench tool. Expasy's Prot-param server and CYC_REC tool were used for physiochemical and functional characterization of the protein. Studied of secondary structure of that protein was carried out by computational program, ProFunc. The structure is finally submitted in Protein Model Database. The predicted model permits initial inferences about the unexplored 3D structure of the CMP kinase and may be promote in relational designing of molecules for structure-function studies.

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Molecular modeling and dynamics studies of cytidylate kinase from Mycobacterium tuberculosis H37Rv

Cited by 16 publications

References 33 publications

Binding dynamics and energetic insight into the molecular forces driving nucleotide binding by guanylate kinase

Binding dynamics and energetic insight into the molecular forces driving nucleotide binding by guanylate kinase

Kinetic mechanism and energetics of binding of phosphoryl group acceptors to Mycobacterium tuberculosis cytidine monophosphate kinase

Insight from the structural molecular model of cytidylate kinase from Mycobacterium tuberculosis

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