Title

Testing High Concentrations of Membrane Active Antibiotic Chlorhexidine Via Computational Titration and Calorimetry

Document Type

Article

Publication Date

5-11-2017

Publication Title

Journal of Physical Chemistry B

Volume

121

Issue

18

First Page

4657

Last Page

4668

Abstract

Coarse-grained strategies for membrane simulations are designed to increase efficiency for larger and more complex molecular dynamics simulations. For membrane active antibiotics, the concentration dependence of their action presents a tremendous challenge in simulation scale. In this study, we examine the effects of concentration for the popular membrane active antibacterial drug chlorhexidine. It presents an interesting biophysical modeling test, where from experimental experience we know that model membranes of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) can absorb very high quantities of the drug without disruption. We construct a coarse-grained model of chlorhexidine in three different charged states and compare to previous all-atom simulations and new experiments. Using large, long-time, and unbiased simulations of chlorhexidine inserting into the lipid bilayer, we find little changes to the functional structure of a DMPC membrane up through concentrations of 15:100 drug:lipid, where the slowing rate of continued insertion tests the capabilities of even this coarse-grained approach. We validate our simulations with computational calorimetry measurements, and show that they agree with new experimental data from differential scanning calorimetry.

DOI

10.1021/acs.jpcb.6b12510

ISSN

15206106

E-ISSN

15205207

PubMed ID

28425718

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