Visualization and analysis of non-covalent contacts using the Protein Contacts Atlas

Abstract

Visualizations of biomolecular structures empower us to gain insights into biological functions, generate testable hypotheses, and communicate biological concepts. Typical visualizations (e.g. ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiology, pathogenesis, and drug action, are seldom visualized. We present Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and analysis of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes. Protein Contacts Atlas enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces and protein-ligand contacts, and by mapping external information. Protein Contacts Atlas is available at http://www.mrc-lmb.cam.ac.uk/pca/ and also through PDBe.

Uncovering patterns of atomic interactions in static and dynamic structures of proteins

“…Studying atomic interactions in protein structures has been a useful approach, and different tools have been developed to enable computing and analyzing interactions in individual structures (Nishikawa et al 1972;Kayikci et al 2018) . However, the true potential of interaction analysis lies in being able to perform comparisons across many structures and identify patterns that can be exploited.…”

“…However, the true potential of interaction analysis lies in being able to perform comparisons across many structures and identify patterns that can be exploited. GetContacts and Contact Comparison Atlas build upon the strengths of previously available tools (Kayikci et al 2018) and enable comparisons across multiple structures and simulations. They also enable efficient analysis of very large quantities of simulation and structure data.…”

“…missense mutations in protein coding regions) between individuals. Comparing the residue interactions in functional regions can help with identifying disease-associated mutations from other mutations (Kayikci et al 2018) (Hauser et al 2018) .…”

“…In such comparative analyses of protein structures and simulations, focusing on patterns of atomic interactions ( e.g. hydrogen bonds) enables us to gain an in-depth understanding of function (Kayikci et al 2018) (Doncheva et al 2011) (Zhang, Perica, and Teichmann 2013) (Vass, Podlewska, et al 2018) . For instance, studying patterns of interactions can help identify amino acid residues important for ligand-binding (Venkatakrishnan et al 2013) (Ngo et al 2017) , understand similarities in activation mechanisms (Venkatakrishnan et al 2016) and understand specificity in protein interactions (Flock et al 2015) .…”

Functional and Early Folding Residues are separated in proteins to increase evolvability and robustness

“…Residues which are protected from the 46 exchange at the earliest stages [14,[37][38][39] are called Early Folding Residues (EFR). 47 Residues which became protected at later stages or not at all are referred to as Late 48 Folding Residues (LFR). EFR were shown to initiate the folding process and the 49 formation of secondary structure elements [39] or even larger autonomously folding 50 units [14].…”