Ligand Unbinding Pathway and Mechanism Analysis Assisted by Machine Learning and Graph Methods

J Chem Inf Model. 2022 Oct 10;62(19):4591-4604. doi: 10.1021/acs.jcim.2c00634. Epub 2022 Sep 29.

Abstract

We present two methods to reveal protein-ligand unbinding mechanisms in biased unbinding simulations by clustering trajectories into ensembles representing unbinding paths. The first approach is based on a contact principal component analysis for reducing the dimensionality of the input data, followed by identification of unbinding paths and training a machine learning model for trajectory clustering. The second approach clusters trajectories according to their pairwise mean Euclidean distance employing the neighbor-net algorithm, which takes into account input data bias in the distances set and is superior to dendrogram construction. Finally, we describe a more complex case where the reaction coordinate relevant for path identification is a single intraligand hydrogen bond, highlighting the challenges involved in unbinding path reaction coordinate detection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Kinetics
  • Ligands
  • Machine Learning*
  • Protein Binding
  • Proteins* / chemistry

Substances

  • Ligands
  • Proteins