StructureDistiller: Structural relevance scoring identifies the most informative entries of a contact map

Abstract

Protein folding and structure prediction are two sides of the same coin. Contact maps and the related techniques of constraint-based structure reconstruction can be considered as unifying aspects of both processes. We present the Structural Relevance (SR) score which quantifies the information content of individual contacts and residues in the context of the whole native structure. The physical process of protein folding is commonly characterized with spatial and temporal resolution: some residues are Early Folding while others are Highly Stable with respect to unfolding events. We employ the proposed SR score to demonstrate that folding initiation and structure stabilization are subprocesses realized by distinct sets of residues. The example of cytochrome c is used to demonstrate how StructureDistiller identifies the most important contacts needed for correct protein folding. This shows that entries of a contact map are not equally relevant for structural integrity. The proposed StructureDistiller algorithm identifies contacts with the highest information content; these entries convey unique constraints not captured by other contacts. Identification of the most informative contacts effectively doubles resilience toward contacts which are not observed in the native contact map. Furthermore, this knowledge increases reconstruction fidelity on sparse contact maps significantly by 0.4 Å.

Structural Comparison of the SARS CoV 2 Spike Protein Relative to Other Human-Infecting Coronaviruses

“…To further differentiate SARS2 and other human-infecting CoV spike models, contact map overlap (CMO) analyses were done. Contact maps provide information with regards to the pairwise spatial and functional relationship of residues in a given protein and, likewise, unifies certain aspects of protein folding and structure prediction which in-turn allows protein reconstruction ( 33 , 34 ). We found that among the CoV spike models compared to SARS2 model ( Figures 3D–I ), only SARS1 has more common contact (89.2%) with SARS2 ( Figure 3H ) which in-turn would indicate that SARS1 and SARS2 spike models have high structural similarity compared to SARS2 and other human-infecting CoV spike models (common contact <50%).…”

Structural patterns of SARS-CoV-2 variants of concern (alpha, beta, gamma, delta) spike protein are influenced by variant-specific amino acid mutations: A computational study with implications on viral evolution

“…3 ). TM score measurements mainly focuses on structural similarities between proteins without regard to protein size ( Kufareva and Abagyan, 2012 , Zhang and Skolnick, 2005 ), whereas, CMO analyses (through common contact measurements) give relevant information with regard to the pairwise spatial and functional relationship of residues within a protein ( Bittrich et al, 2019 , Wang and Xu, 2013 ).

Figure 3 Certain combination of variant-specific amino acid residue mutations possibly influence SARS-CoV-2 variant of concern spike protein structural patterns.

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Structural Insights on the SARS-CoV-2 Variants of Concern Spike Glycoprotein: A Computational Study With Possible Clinical Implications

“…Measurements involving RMSD values focus on similarities between superimposed atomic coordinates (including amino acid residues), whereas, measurements involving TM scores focus on similarities between protein structures regardless of protein size (Zhang and Skolnick, 2005;Kufareva and Abagyan, 2012). Additionally, common contacts obtained through CMO analyses provide information related to pairwise spatial and functional relationship of residues within a protein while unifying certain features related to protein folding and structure prediction (Wang and Xu, 2013;Bittrich et al, 2019). Original SARS2 and VOC spike models used were generated by Phyre2 (Supplementary Figure S1).…”