Self-Organizing Maps of Unbiased Ligand-Target Binding Pathways and Kinetics

TL;DR

This paper introduces a novel application of Self-Organizing Maps (SOM) to analyze unbiased molecular dynamics simulations, providing detailed insights into ligand-target binding pathways and kinetics, which enhances drug discovery efforts.

Contribution

The study presents a new SOM-based method for mapping ligand-target interactions from unbiased MD simulations, addressing sampling challenges and integrating kinetic analysis tools.

Findings

Successfully mapped 640 μs of unbiased MD trajectories.

Revealed detailed ligand recognition pathways and induced fit effects.

Enhanced understanding of binding kinetics and mechanisms.

Abstract

The interpretation of ligand-target interactions at atomistic resolution is central to most efforts in computational drug discovery and optimization. However, the highly dynamic nature of protein targets, as well as possible induced fit effects, makes difficult to sample many interactions effectively with docking studies or even with large-scale molecular dynamics (MD) simulations. We propose a novel application of Self-Organizing Maps (SOM) to address the sampling and dynamic mapping tasks, particularly in cases involving ligand flexibility and induced fit. The SOM approach offers a data-driven strategy to create a map of the interaction process and pathways based on unbiased MD. Furthermore, we show how the preliminary SOM mapping is complementary to kinetic analysis, both with the employment of network-based approaches and Markov State Models (MSM). We demonstrate the method by comprehensively mapping a large dataset of 640 {\mu}s of unbiased trajectories sampling the recognition process between the phosphorylated YEEI peptide and its high-specificity target Lck-SH2. The integration of SOM into unbiased simulation protocols significantly advances our understanding of the ligand binding mechanism. This approach serves as a potent tool for mapping intricate ligand-target interactions with unprecedented detail, thereby enhancing the characterization of kinetic properties crucial to drug design.