Solution and Crystal Molecular Dynamics Simulation Study of m4-Cyanovirin-N Mutants Complexed with Di-Mannose
| Autor: | Osamu Miyashita, Ivan I. Vorontsov |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Anti-HIV Agents Protein Conformation Stereochemistry Biophysics Glutamic Acid Mannose HIV Envelope Protein gp120 Arginine Crystallography X-Ray Crystal chemistry.chemical_compound Molecular dynamics Protein structure Bacterial Proteins Humans Computer Simulation Binding site Binding Sites biology Hydrogen bond Protein Hydrogen Bonding Ligand (biochemistry) Crystallography Cyanovirin-N chemistry Mutation biology.protein Carrier Proteins |
| Zdroj: | Biophysical Journal. 97:2532-2540 |
| ISSN: | 0006-3495 |
| Popis: | Cyanovirin-N (CVN) is a highly potent anti-HIV carbohydrate-binding agent that establishes its microbicide activity through interaction with mannose-rich glycoprotein gp120 on the virion surface. The m4-CVN and P51G-m4-CVN mutants represent simple models for studying the high-affinity binding site, BM. A recently determined 1.35 Å high-resolution structure of P51G-m4-CVN provided details on the di-mannose binding mechanism, and suggested that the Arg-76 and Glu-41 residues are critical components of high mannose specificity and affinity. We performed molecular-dynamics simulations in solution and a crystal environment to study the role of Arg-76. Network analysis and clustering were used to characterize the dynamics of Arg-76. The results of our explicit solvent solution and crystal simulations showed a significant correlation with conformations of Arg-76 proposed from x-ray crystallographic studies. However, the crystal simulation showed that the crystal environment strongly biases conformational sampling of the Arg-76 residue. The solution simulations demonstrated no conformational preferences for Arg-76, which would support its critical role as the residue that locks the ligand in the bound state. Instead, a comparative analysis of trajectories from >50 ns of simulation for two mutants revealed the existence of a very stable eight-hydrogen-bond network between the di-mannose ligand and predominantly main-chain atoms. This network may play a key role in the specific recognition and strong binding of mannose oligomers in CVN and its homologs. |
| Databáze: | OpenAIRE |
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