Structure, dynamics, and interaction of Mycobacterium tuberculosis (Mtb) DprE1 and DprE2 examined by molecular modeling, simulation, and electrostatic studies

PloS One
Isha BhutaniRaman Parkesh

Abstract

The enzymes decaprenylphosphoryl-β-D-ribose oxidase (DprE1) and decaprenylphosphoryl-β-D-ribose-2-epimerase (DprE2) catalyze epimerization of decaprenylphosporyl ribose (DPR) todecaprenylphosporyl arabinose (DPA) and are critical for the survival of Mtb. Crystal structures of DprE1 so far reported display significant disordered regions and no structural information is known for DprE2. We used homology modeling, protein threading, molecular docking and dynamics studies to investigate the structural and dynamic features of Mtb DprE1 and DprE2 and DprE1-DprE2 complex. A three-dimensional model for DprE2 was generated using the threading approach coupled with ab initio modeling. A 50 ns simulation of DprE1 and DprE2 revealed the overall stability of the structures. Principal Component Analysis (PCA) demonstrated the convergence of sampling in both DprE1 and DprE2. In DprE1, residues in the 269-330 area showed considerable fluctuation in agreement with the regions of disorder observed in the reported crystal structures. In DprE2, large fluctuations were detected in residues 95-113, 146-157, and 197-226. The study combined docking and MD simulation studies to map and characterize the key residues involved in DprE1-DprE2 interaction. ...Continue Reading

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Citations

Apr 25, 2018·Antimicrobial Agents and Chemotherapy·Lu XiongLuo-Ting Yu
Mar 11, 2016·Genes & Genetic Systems·Félix F González-NavarroGabriel A López-Morteo
Sep 26, 2020·Frontiers in Plant Science·Samara Oña ChuquimarcaMiguel Ángel Méndez
Dec 18, 2020·Frontiers in Chemistry·Krishnasamy GopinathOlli T Pentikäinen
Jan 23, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rafael BaptistaLuis A J Mur

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Methods Mentioned

BETA
X-ray
PCA
sequence-based prediction

Software Mentioned

STRING
SALIGN
Ligplot +
ClusPro
GRAMM
GROMACS
COCOMAPS
Gor4
ModLoop
AutoGrid

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