Issue 16, 2022

Data-driven discovery of cardiolipin-selective small molecules by computational active learning

Abstract

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 ≈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.

Graphical abstract: Data-driven discovery of cardiolipin-selective small molecules by computational active learning

Supplementary files

Article information

Article type
Edge Article
Submitted
06 1月 2022
Accepted
24 2月 2022
First published
02 3月 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 4498-4511

Data-driven discovery of cardiolipin-selective small molecules by computational active learning

B. Mohr, K. Shmilovich, I. S. Kleinwächter, D. Schneider, A. L. Ferguson and T. Bereau, Chem. Sci., 2022, 13, 4498 DOI: 10.1039/D2SC00116K

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