Dataset Information

Homology modeling and molecular dynamics simulation of odonthubuthus doriae (Od1) scorpion toxin in comparison to the BmK M1.

ABSTRACT: All of the ?-subgroups share similarity in their sequence and structure but different in the toxicity to various voltage-gated sodium channels (VGSCs). We modeled the first 3D structural model of the Od1 based on BmK M1 using homology modeling. The reliability of model for more investigation and compare to BmK M1 has been examined and confirmed. Then the model structure is further refined by energy minimization and molecular dynamics methods. The purpose of this modeling and simulation is comparison toxicity of two mentioned toxins by investigation structural feature of functional regions including core domain, 5-turn and C-terminal which make NC domain. In the one hand, it is intriguing that Od1 in comparison to BmK M1 shows same solvent accessible surface area (SASA) in 5-turn region but a little more exposed and feasibility (more SASA) in C-terminal region and key functional residues of C-terminal such as positive residues Arg58, lys62 and Arg (His)64. These data suggested that Od1 has similarity with BmK M1 but has more toxicity to sodium channel. In the other hand 5-turn proximity of C-terminal to 5-turn in BmK M1with cis peptide bond is less than Od1 without cis peptide bond which is a confirmation with experimental data about BmK M1.A better understanding of the 3-D structure of Od1and comparison to BmK M1 will be helpful for more investigation of functional characters action of natural toxins with a specialized role for VGSCs.

SUBMITTER: Karimi Z

PROVIDER: S-EPMC3374358 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Homology modeling and molecular dynamics simulation of odonthubuthus doriae (Od1) scorpion toxin in comparison to the BmK M1.

Karimi Zahra Z Falsafi-Zadeh Sajad S Galehdari Hamid H Jalali Amir A

Bioinformation 20120531 10

All of the α-subgroups share similarity in their sequence and structure but different in the toxicity to various voltage-gated sodium channels (VGSCs). We modeled the first 3D structural model of the Od1 based on BmK M1 using homology modeling. The reliability of model for more investigation and compare to BmK M1 has been examined and confirmed. Then the model structure is further refined by energy minimization and molecular dynamics methods. The purpose of this modeling and simulation is compar ...[more]

PMID: 22715302

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Project description:The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with activity as hTRPV1 antagonists, several of which showed substantial potency.

Dataset Information

Homology modeling and molecular dynamics simulation of odonthubuthus doriae (Od1) scorpion toxin in comparison to the BmK M1.

Publications

Homology modeling and molecular dynamics simulation of odonthubuthus doriae (Od1) scorpion toxin in comparison to the BmK M1.

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