Molecular dynamics simulation of bovine prothrombin fragment 1 in the presence of calcium ions

Abstract

Early solvation-induced structural reorganization of calcium prothrombin fragment 1 is simulated with molecular dynamics. Initial coordinates are those of the 2.2-A resolution crystal structure [Soriano-Garcia, M., Padmanabhan, K., de Vos, A. M., & Tulinsky, A. (1992) Biochemistry 31, 2554-2556]. The molecular dynamics code AMBER, appropriately modified to include long-range (less than or equal to 22.0 A) ionic forces, was employed. The solution structure appears to equilibrate within 100 ps. Although minor changes are seen in various structural domains, the early solution structure basically maintains an intricate network of nine gamma-carboxyglutamic acid (Gla) residues encapsulating seven calcium ions. However, the Gla domain moves with respect to the kringle domain. This motion is mainly due to the movement of Ser34-Leu35 that appears to be a flexible hinge between the domains. The N-terminus of Ala 1 is in a tightly bound complex with three Gla residues that remains stable in the solution structure when the long-range electrostatic cutoff is employed and the near planar alignment of the seven calcium ions is only slightly distorted. The simulation structure is discussed in terms of experiments that studied calcium ion-induced quenching of the intrinsic fluorescence, protection of the N-terminal amino group from acetylation by calcium ions, chemical modification of the N-terminus to a trinitrophenyl derivative, and the possibility of a calcium-binding site(s) in the kringle domain.

Homology Modeling and Molecular Dynamics Simulations of the Gla Domains of Human Coagulation Factor IX and Its G[12]A Mutant

“…24 In addition, we also computationally mutated Gly12 to Ala in a separate simulation. Hemophilia B is a classification for bleeding disorders that result from mutations in factor IX; G [12]A is one of these naturally occurring mutations. 30 Since Gly12 is largely conserved in human vitamin K-dependent proteins, it is of considerable interest to examine the effect of the mutation on the global structure.…”

Predicted solution structure of zymogen human coagulation FVII

“…These combined Gla/EGF1, EGF1/EGF2 domains and the light chain or entire protein show larger magnitudes in their RMSD values than the individual domains. As has been pointed out earlier, 39 such deviations may arise due to relative domain motions even though individual domain structures remain relatively near those of the X-ray crystal structure. When the combined domain RMSDs are considered, the net reorganization effect is amplified.…”

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

“…Mo.). The procedures for the modeling were similar to those reported pre viously [9]. The molecular dynamics code used was AMBER 3.0A [10], Gla domain (residues 1-33) and the connect ing region (residues 34-64 to the core of the Gla domain and maintain ing the appropriate shape of the loop for PL binding [11][12][13][14], While Ca-4 and Ca-5 re mained associated with Alal-N in both wild type (avg-hfl/Ca) and X[6]D mutant (avg-X[6]D hfl/Ca) simulations, the contact be tween Alal-N and Ca-4 in the X [16]D was lost (table 1).…”

“…As a result, (1) the short helix (Leu 13-Asp 16) was lost, (2) figure 1. Collectively, the change of the shape of the co-loop, loss of contact between the Gla do main and the connecting region (34-65), and decreased stability of both the Gla and kringle domains in the X [16]D mutant may explain the loss of coagulation activity of this mutant [9].…”