期刊
CHEMICAL SCIENCE
卷 13, 期 16, 页码 4498-4511出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2sc00116k
关键词
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资金
- Sectorplan B`eta & Techniek of the Dutch Government
- National Science Foundation's Graduate Research Fellowship [DGE-1746045]
- DynaMem (State of Rhineland-Palatinate, Germany)
- University of Chicago Research Computing Center
- National Science Foundation [DMR-1828629, DMS-1440415]
Subtle variations in lipid composition of mitochondrial membranes have a profound impact on mitochondrial function. This study combines deep learning-enabled active learning, molecular dynamics simulations, and free energy calculations to discover small organic compounds that can selectively permeate cardiolipin-containing membranes. The findings highlight the potential of coarse-grained representations and multiscale modeling for materials discovery and design.
Subtle variations in the lipid composition of mitochondrial membranes can have a profound impact on mitochondrial function. The inner mitochondrial membrane contains the phospholipid cardiolipin, which has been demonstrated to act as a biomarker for a number of diverse pathologies. Small molecule dyes capable of selectively partitioning into cardiolipin membranes enable visualization and quantification of the cardiolipin content. Here we present a data-driven approach that combines a deep learning-enabled active learning workflow with coarse-grained molecular dynamics simulations and alchemical free energy calculations to discover small organic compounds able to selectively permeate cardiolipin-containing membranes. By employing transferable coarse-grained models we efficiently navigate the all-atom design space corresponding to small organic molecules with molecular weight less than approximate to 500 Da. After direct simulation of only 0.42% of our coarse-grained search space we identify molecules with considerably increased levels of cardiolipin selectivity compared to a widely used cardiolipin probe 10-N-nonyl acridine orange. Our accumulated simulation data enables us to derive interpretable design rules linking coarse-grained structure to cardiolipin selectivity. The findings are corroborated by fluorescence anisotropy measurements of two compounds conforming to our defined design rules. Our findings highlight the potential of coarse-grained representations and multiscale modelling for materials discovery and design.
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