Exploring putative enteric methanogenesis inhibitors using molecular simulations and a graph neural network

Abstract

Atmospheric methane (CH4) acts as a key contributor to global warming. As CH4 is a short-lived climate forcer (12 years atmospheric lifespan), its mitigation represents the most promising means to address climate change in the short term. Enteric CH4 (the biosynthesized CH4 from the rumen of ruminants) represents 5.1% of total global greenhouse gas (GHG) emissions, 23% of emissions from agriculture, and 27.2% of global CH4 emissions. Therefore, it is imperative to investigate methanogenesis inhibitors and their underlying modes of action. We hereby elucidate the detailed biophysical and thermodynamic interplay between anti-methanogenic molecules and cofactor F430 of methyl coenzyme M reductase and interpret the stoichiometric ratios and binding affinities of sixteen inhibitor molecules. We leverage this as prior in a graph neural network to first functionally cluster these sixteen known inhibitors among [~]54,000 bovine metabolites. We subsequently demonstrate a protocol to identify precursors to and putative inhibitors for methanogenesis, based on Tanimoto chemical similarity and membrane permeability predictions. This work lays the foundation for computational and de novo design of inhibitor molecules that retain/ reject one or more biochemical properties of known inhibitors discussed in this study. COVER ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/613350v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1fd4518org.highwire.dtl.DTLVardef@c34d87org.highwire.dtl.DTLVardef@16eef9org.highwire.dtl.DTLVardef@1a33512_HPS_FORMAT_FIGEXP M_FIG C_FIG