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Characterizing the protonation states of the catalytic residues in apo and substrate-bound human T-cell leukemia virus type 1 protease

Paper ID Volume ID Publish Year Pages File Format Full-Text
15058 1370 2015 10 PDF Available
Title
Characterizing the protonation states of the catalytic residues in apo and substrate-bound human T-cell leukemia virus type 1 protease
Abstract

•Protonation states of the catalytic residues in HTLV-1 protease were investigated.•In apo HTLV-1 protease, the two catalytic residues are both unprotonated.•In HTLV-1 protease–substrate complex, Asp32 is protonated, Asp32′ is unprotonated.•Substrate binding favors a protonated Asp32 over protonated Asp32′ by 2.8 kcal/mol.•The HTLV-1 protease–substrate complex structure was analyzed in detail.

Human T-cell leukemia virus type 1 (HTLV-1) protease is an attractive target when developing inhibitors to treat HTLV-1 associated diseases. To study the catalytic mechanism and design novel HTLV-1 protease inhibitors, the protonation states of the two catalytic aspartic acid residues must be determined. Free energy simulations have been conducted to study the proton transfer reaction between the catalytic residues of HTLV-1 protease using a combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulation. The free energy profiles for the reaction in the apo-enzyme and in an enzyme – substrate complex have been obtained. In the apo-enzyme, the two catalytic residues are chemically equivalent and are expected to be both unprotonated. Upon substrate binding, the catalytic residues of HTLV-1 protease evolve to a singly protonated state, in which the OD1 of Asp32 is protonated and forms a hydrogen bond with the OD1 of Asp32′, which is unprotonated. The HTLV-1 protease–substrate complex structure obtained from this simulation can serve as the Michaelis complex structure for further mechanistic studies of HTLV-1 protease while providing a receptor structure with the correct protonation states for the active site residues toward the design of novel HTLV-1 protease inhibitors through virtual screening.

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Keywords
HTLV-1 protease; Catalytic residues; Protonation states; Free energy simulations; QM/MM
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Characterizing the protonation states of the catalytic residues in apo and substrate-bound human T-cell leukemia virus type 1 protease
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Publisher
Database: Elsevier - ScienceDirect
Journal: Computational Biology and Chemistry - Volume 56, June 2015, Pages 61–70
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us