Adaptive Partitioning QM/MM Dynamics Simulations for Substrate Uptake, Product Release, and Solvent Exchange

2016 ◽  
pp. 341-357 ◽  
Author(s):  
A. Duster ◽  
C. Garza ◽  
H. Lin
Keyword(s):  
Substrate Uptake ◽  
Solvent Exchange ◽  
Product Release ◽  
Adaptive Partitioning ◽  
Dynamics Simulations

scholarly journals The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release

2018 ◽  
Vol 293 (21) ◽  
pp. 7969-7981 ◽  
Author(s):  
Thomas E. Bohl ◽  
Pek Ieong ◽  
John K. Lee ◽  
Thomas Lee ◽  
Jayakanth Kankanala ◽  
...  
Keyword(s):  
Rational Design ◽  
Substrate Binding ◽  
Flexible Substrate ◽  
Binding Mode ◽  
Antibiotic Development ◽  
Product Release ◽  
Outer Leaflet ◽  
Hydrogen Deuterium ◽  
Dynamics Simulations ◽  
Secondary Membrane

Gram-negative bacteria are surrounded by a secondary membrane of which the outer leaflet is composed of the glycolipid lipopolysaccharide (LPS), which guards against hydrophobic toxins, including many antibiotics. Therefore, LPS synthesis in bacteria is an attractive target for antibiotic development. LpxH is a pyrophosphatase involved in LPS synthesis, and previous structures revealed that LpxH has a helical cap that binds its lipid substrates. Here, crystallography and hydrogen–deuterium exchange MS provided evidence for a highly flexible substrate-binding cap in LpxH. Furthermore, molecular dynamics simulations disclosed how the helices of the cap may open to allow substrate entry. The predicted opening mechanism was supported by activity assays of LpxH variants. Finally, we confirmed biochemically that LpxH is inhibited by a previously identified antibacterial compound, determined the potency of this inhibitor, and modeled its binding mode in the LpxH active site. In summary, our work provides evidence that the substrate-binding cap of LpxH is highly dynamic, thus allowing for facile substrate binding and product release between the capping helices. Our results also pave the way for the rational design of more potent LpxH inhibitors.

Adaptive Partitioning QM/MM for Molecular Dynamics Simulations: 6. Proton Transport through a Biological Channel

2019 ◽  
Vol 15 (2) ◽  
pp. 892-905 ◽  
Author(s):  
Adam W. Duster ◽  
Christina M. Garza ◽  
Baris O. Aydintug ◽  
Mikias B. Negussie ◽  
Hai Lin
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Proton Transport ◽  
Adaptive Partitioning ◽  
Dynamics Simulations

scholarly journals Lipid-Uptake Pathways and Lipid-Protein interactions in P-glycoprotein Revealed by Coarse-Grained Molecular Dynamics Simulations

2017 ◽  
Author(s):  
E. Barreto-Ojeda ◽  
V. Corradi ◽  
R.-X. Gu ◽  
D.P. Tieleman
Keyword(s):  
Molecular Dynamics ◽  
Protein Interactions ◽  
Experimental Studies ◽  
Md Simulations ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Substrate Uptake ◽  
Lipid Uptake ◽  
P Glycoprotein ◽  
Dynamics Simulations

AbstractP-glycoprotein (P-gp) exports a broad range of dissimilar compounds, including drugs, lipids and lipid-like molecules. Due to its substrate promiscuity, P-gp is a key player in the development of cancer multidrug resistance (MDR). Although P-gp is one of the most studied members of ABC-transporters, the mechanism of how its substrates access the cavity remains unclear. In this work, we performed coarse-grained (CG) molecular dynamics (MD) simulations to explore possible pathways of lipid-uptake in the inward-facing conformation of P-gp embedded in bilayers with different PC:PE lipid ratios. Our results show that in the inward facing orientation only lipids from the lower leaflet are taken up by the transporter. We identify positively charged residues at the portals of P-gp that favor lipid entrance to the cavity, as well as lipid binding sites, in good agreement with previous experimental studies. Our results show no selectivity for PC vs. PE lipids. We offer several examples of lipid uptake-pathways for PC and PE lipids that help to elucidate the molecular mechanism of substrate-uptake in P-gp.

Sign in / Sign up

Export Citation Format

Share Document