Abstract:
:Mycolactone, a cytotoxic and immunosuppressive macrolide produced by Mycobacterium ulcerans, is the central virulent factor in the skin disease Buruli ulcer. This multifunctional cytotoxin affects fundamental cellular processes such as cell adhesion, immune response, and cell death by targeting various cellular structures. Developing effective diagnostics that target mycolactone has been challenging, potentially because of suspected interactions with lipophilic architectures, including membranes. To better understand the pathogenesis of Buruli ulcer disease, aid in the development of diagnostics, and learn how amphiphiles in general use lipid trafficking to navigate the host environment, we seek to understand the nature of mycolactone-membrane interactions. Herein, we characterize how the two dominant isomers of mycolactone (A and B) interact with and permeate DPPC membranes with all-atom molecular dynamics simulations employing transition-tempered metadynamics and compare these results to those obtained by MARTINI coarse-grained simulations. Our all-atom simulations reveal that both isomers have a strong preference to associate with the membrane, although their mechanisms and energetics of membrane permeation differ slightly. Water molecules are found to play an important role in the permeation process. Although the MARTINI coarse-grained simulations give the correct free energy of membrane association, they fail to capture the mechanism of permeation and role of water during permeation as seen in all-atom simulations.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Aydin F,Sun R,Swanson JMJdoi
10.1016/j.bpj.2019.05.012subject
Has Abstractpub_date
2019-07-09 00:00:00pages
87-98issue
1eissn
0006-3495issn
1542-0086pii
S0006-3495(19)30414-Xjournal_volume
117pub_type
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