Computational Studies of Human Prothrombin Fragment 1 the Gla Domain of Factor IX and Several Biological Interesting Mutants

Li, Leping; Darden, Tom; Hiskey, Richard G.; Pedersen, Lee G.

doi:10.1159/000217241

Cited by 2 publications

(1 citation statement)

References 8 publications

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“…The root mean square deviations (RMSDs) of backbone atoms from their initial positions (t ϭ 0 ps) have been used to measure the stability of the simulation and to provide insight into possible structure fluctuations (Hamaguchi et al, 1992;Li et al, 1996;Perera et al, 1997). The RMSDs for the complete protein and for certain selected substructural domains are presented in Fig.…”

Section: Global Aspects Of the Simulationmentioning

confidence: 99%

Modeling Zymogen Protein C

Perera

Foley

Darden

et al. 2000

Biophysical Journal

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A solution structure for the complete zymogen form of human coagulation protein C is modeled. The initial core structure is based on the x-ray crystallographic structure of the gamma-carboxyglutamic acid (Gla)-domainless activated form. The Gla domain (residues 1-48) is modeled from the x-ray crystal coordinates of the factor VII(a)/tissue factor complex and oriented with the epidermal growth factor-1 domain to yield an initial orientation consistent with the x-ray crystal structure of porcine factor IX(a). The missing C-terminal residues in the light chain (residues 147-157) and the activation peptide residues 158-169 were introduced using homology modeling so that the activation peptide residues directly interact with the residues in the calcium binding loop. Molecular dynamics simulations (Amber-particle-mesh-Ewald) are used to obtain the complete calcium-complexed solution structure. The individual domain structures of protein C in solution are largely unaffected by solvation, whereas the Gla-epidermal growth factor-1 orientation evolves to a form different from both factors VII(a) and IX(a). The solution structure of the zymogen protein C is compared with the crystal structures of the existing zymogen serine proteases: chymotrypsinogen, proproteinase, and prethrombin-2. Calculated electrostatic potential surfaces support the involvement of the serine protease calcium ion binding loop in providing a suitable electrostatic environment around the scissile bond for II(a)/thrombomodulin interaction.

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Section: Global Aspects Of the Simulationmentioning

confidence: 99%

Modeling Zymogen Protein C

Perera

Foley

Darden

et al. 2000

Biophysical Journal

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Probing the Structural Changes in the Light Chain of Human Coagulation Factor VIIa Due to Tissue Factor Association

Perera

Darden

Pedersen

1999

Biophysical Journal

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The crystallographic structure of human coagulation factor VIIa/tissue factor complex bound with calcium ions was used to model the solution structure of the light chain of factor VIIa (residues 1-142) in the absence of tissue factor. The Amber force field in conjunction with the particle mesh Ewald summation method to accommodate long-range electrostatic interactions was used in the trajectory calculations. The estimated TF-free solution structure was then compared with the crystal structure of factor VIIa/tissue factor complex to estimate the restructuring of factor VIIa due to tissue factor binding. The solution structure of the light chain of factor VIIa in the absence of tissue factor is predicted to be an extended domain structure similar to that of the tissue factor-bound crystal. Removal of the EGF1-bound calcium ion is shown by simulation to lead to minor structural changes within the EGF1 domain, but also leads to substantial relative reorientation of the Gla and EGF1 domains.

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Computational Studies of Human Prothrombin Fragment 1 the Gla Domain of Factor IX and Several Biological Interesting Mutants

Cited by 2 publications

References 8 publications

Modeling Zymogen Protein C

Modeling Zymogen Protein C

Probing the Structural Changes in the Light Chain of Human Coagulation Factor VIIa Due to Tissue Factor Association

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