Identifying and profiling structural similarities between Spike of SARS-CoV-2 and other viral or host proteins with Machaon

Abstract

Using protein structure to predict function, interactions, and evolutionary history is still an open challenge, with existing approaches relying extensively on protein homology and families. Here, we present Machaon, a data-driven method combining orientation invariant metrics on phi-psi angles, inter-residue contacts and surface complexity. It can be readily applied on whole structures or segments—such as domains and binding sites. Machaon was applied on SARS-CoV-2 Spike monomers of native, Delta and Omicron variants and identified correlations with a wide range of viral proteins from close to distant taxonomy ranks, as well as host proteins, such as ACE2 receptor. Machaon’s meta-analysis of the results highlights structural, chemical and transcriptional similarities between the Spike monomer and human proteins, indicating a multi-level viral mimicry. This extended analysis also revealed relationships of the Spike protein with biological processes such as ubiquitination and angiogenesis and highlighted different patterns in virus attachment among the studied variants. Available at: https://machaonweb.com.

Comparative structural insights and functional analysis for the distinct unbound states of Human AGO proteins

“…As function is connected to structure, we performed whole structure comparisons via Machaon 55 between the AGOs, scanning two large datasets of human protein structures: ~183000 PDB chains from RCSB 56 (HL2 -Human protein list 2, Supplementary Data 5) and ~25000 human protein structures from AlphaFoldDB 57 (AF4 -AlphaFold version 4 Homo sapiens dataset). We included the representative conformations from the clustered trajectories of the reference protein per each session, enhancing the selection of the most structurally similar proteins from each dataset.…”

“…We employed Metal3D 53 to predict zinc ion binding sites and PocketMiner 52 to predict binding pockets in the preprocessed AGO protein structures. We identified structurally similar structures to the preprocessed AGO protein structures by whole structure searches and we performed constrained structural searches for AGO2 PIWI domain via Machaon 55 . For every search, we included the clustered trajectories of the reference protein in the search space until the formation of the clusters.…”