Solution conformations of the gamma-carboxyglutamic acid domain of bovine prothrombin fragment 1, residues 1-65
| Autor: | Lee G. Pedersen, Tom Darden, Joseph L. Hughey, Richard G. Hiskey, Alexander Tulinsky, Paul S. Charifson |
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| Rok vydání: | 1991 |
| Předmět: |
Models
Molecular Protein Conformation Stereochemistry chemistry.chemical_element Crystal structure Calorimetry Calcium Molecular dynamics Protein structure Animals Peptide bond Computer Simulation Conformational isomerism Binding Sites Multidisciplinary Intermolecular force Peptide Fragments Solutions Crystallography chemistry Cattle Prothrombin 1-Carboxyglutamic Acid Isomerization Research Article |
| Zdroj: | Proceedings of the National Academy of Sciences. 88:424-428 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.88.2.424 |
| Popis: | Molecular dynamics simulations have been performed (AMBER version 3.1) on solvated residues 1-65 of bovine prothrombin fragment 1 (BF1) by using the 2.8-A resolution crystallographic coordinates as the starting conformation for understanding calcium ion-induced conformational changes that precede experimentally observable phospholipid binding. Simulations were performed on the non-metal-bound crystal structure, the form resulting from addition of eight calcium ions to the 1-65 region of the crystal structure, the form resulting from removal of calcium ions after 107 ps and continuing the simulation, and an isolated hexapeptide loop (residues 18-23). In all cases, the 100-ps time scale seemed adequate to sample an ensemble of solution conformers within a particular region of conformation space. The non-metal-containing BF1 did not unfold appreciably during a 106-ps simulation starting from the crystallographic geometry. The calcium ion-containing structure (Ca-BF1) underwent an interesting conformational reorganization during its evolution from the crystal structure: during the time course of a 107-ps simulation, Ca-BF1 experienced a trans----cis isomerization of the gamma-carboxyglutamic acid-21 (Gla-21)-Pro-22 peptide bond. Removal of the calcium ions from this structure followed by 114 ps of additional molecular dynamics showed significant unfolding relative to the final 20-ps average structure of the 107-ps simulation; however, the Gla-21-Pro-22 peptide bond remained cis. A 265-ps simulation on the termini-protected hexapeptide loop (Cys-18 to Cys-23) containing two calcium ions also did not undergo a trans----cis isomerization. It is believed that the necessary activation energy for the transitional event observed in the Ca-BF1 simulation was largely supplied by global conformational events with a possible assist from relief of intermolecular crystal packing forces. The presence of a Gla preceding Pro-22, the inclusion of Pro-22 in a highly strained loop structure, and the formation of two long-lived salt bridges prior to isomerization may all contribute to this finding. |
| Databáze: | OpenAIRE |
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