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Solution and crystal molecular dynamics simulation study of m4-cyanovirin-N mutants complexed with di-mannose.

ABSTRACT: 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, B(M). A recently determined 1.35 A 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.

SUBMITTER: Vorontsov II

PROVIDER: S-EPMC2770623 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Solution and crystal molecular dynamics simulation study of m4-cyanovirin-N mutants complexed with di-mannose.

Vorontsov Ivan I II Miyashita Osamu O

Biophysical journal 20091101 9

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, B(M). A recently determined 1.35 A 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 compone ...[more]

PMID: 19883596

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Project description:Specific interactions between scaffold protein SH3 and multiple ankyrin repeat domains protein 3 (Shank3) and synapse-associated protein 90/postsynaptic density-95?associated protein (SAPAP) are essential for excitatory synapse development and plasticity. In a bunch of human neurological diseases, mutations on Shank3 or SAPAP are detected. To investigate the dynamical and thermodynamic properties of the specific binding between the N-terminal extended PDZ (Post-synaptic density-95/Discs large/Zonaoccludens-1) domain (N-PDZ) of Shank3 and the extended PDZ binding motif (E-PBM) of SAPAP, molecular dynamics simulation approaches were used to study the complex of N-PDZ with wild type and mutated E-PBM peptides. To compare with the experimental data, 974QTRL977 and 966IEIYI970 of E-PBM peptide were mutated to prolines to obtain the M4P and M5P system, respectively. Conformational analysis shows that the canonical PDZ domain is stable while the ?N extension presents high flexibility in all systems, especially for M5P. The high flexibility of ?N extension seems to set up a barrier for the non-specific binding in this area and provide the basis for specific molecular recognition between Shank3 and SAPAP. The wild type E-PBM tightly binds to N-PDZ during the simulation while loss of binding is observed in different segments of the mutated E-PBM peptides. Energy decomposition and hydrogen bonds analysis show that M4P mutations only disrupt the interactions with canonical PDZ domain, but the interactions with ?N1' remain. In M5P system, although the interactions with ?N1' are abolished, the binding between peptide and the canonical PDZ domain is not affected. The results indicate that the interactions in the two-binding site, the canonical PDZ domain and the ?N1' extension, contribute to the binding between E-PBM and N-PDZ independently. The binding free energies calculated by MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) are in agreement with the experimental binding affinities. Most of the residues on E-PBM contribute considerably favorable energies to the binding except A963 and D964 in the N-terminal. The study provides information to understand the molecular basis of specific binding between Shank3 and SAPAP, as well as clues for design of peptide inhibitors.

Dataset Information

Solution and crystal molecular dynamics simulation study of m4-cyanovirin-N mutants complexed with di-mannose.

Publications

Solution and crystal molecular dynamics simulation study of m4-cyanovirin-N mutants complexed with di-mannose.

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