Computational Insights into Allosteric Conformational Modulation of P-Glycoprotein by Substrate and Inhibitor Binding
Abstract
:1. Introduction
2. Results and Discussion
2.1. Different Conformational Changes Mainly Occurred in the NBDs Upon Substrate and Inhibitor Binding to the TMD Cavity
2.2. Conformational Homogeneity in the Substrate- and Inhibitor-Bound States
2.3. Implications of Substrate- and Inhibitor-Coupled Conformational Transitions
2.4. Allosteric Communication between TMDs and NBDs upon Substrate Binding
3. Materials and Methods
3.1. Structural Preparation
3.1.1. Construction of Inhibitor- and Substrate-Bound P-gp Models
3.1.2. Molecular Docking
3.1.3. Preparation of Simulation Systems
3.2. MD Simulations
3.2.1. Simulation Parameters
3.2.2. Simulation Protocol
3.3. Trajectory Analysis
3.3.1. Principal Component Analysis
3.3.2. Cluster Analysis
3.4. Free Energy Calculations
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
P-gp | P-glycoprotein |
TMDs | transmembrane domains |
NBDs | nucleotide-binding domains |
ABC | ATP-binding cassette |
NBSs | nucleotide-binding sites |
MD | molecular dynamics |
RMSDs | root-mean-square deviations |
PCA | principal component analysis |
MM/GBSA | molecular mechanics/generalized born surface area |
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Xing, J.; Huang, S.; Heng, Y.; Mei, H.; Pan, X. Computational Insights into Allosteric Conformational Modulation of P-Glycoprotein by Substrate and Inhibitor Binding. Molecules 2020, 25, 6006. https://doi.org/10.3390/molecules25246006
Xing J, Huang S, Heng Y, Mei H, Pan X. Computational Insights into Allosteric Conformational Modulation of P-Glycoprotein by Substrate and Inhibitor Binding. Molecules. 2020; 25(24):6006. https://doi.org/10.3390/molecules25246006
Chicago/Turabian StyleXing, Juan, Shuheng Huang, Yu Heng, Hu Mei, and Xianchao Pan. 2020. "Computational Insights into Allosteric Conformational Modulation of P-Glycoprotein by Substrate and Inhibitor Binding" Molecules 25, no. 24: 6006. https://doi.org/10.3390/molecules25246006