DOI: 10.5061/dryad.zgmsbcc8g
title: Dataset for article: Co-evolutionary landscape at the interface and non-interface regions of protein-protein interaction complexes

description: Proteins involved in interactions throughout the course of evolution tend
 to co-evolve and compensatory changes may occur in interacting
 proteins to main­tain or refine such interactions. However, certain
 residue pair alterations may prove to be detrimental for functional
 interactions. Hence, determining co-evolutionary pairings that could be
 structurally or functionally relevant for maintaining the conservation of
 an inter-protein interaction is important. Inter-protein co-evolution
 analysis in several complexes utilizing multiple existing methodologies
 suggested that co-evolutionary pairings can occur in spatially proximal
 and distant regions in inter-protein interactions.
 Subsequently, the Co-Var (Correlated Variation) method based on
 mutual information and Bhattacharyya coefficient was developed, validated,
 and found to perform relatively better than CAPS and EV-complex.
 Interestingly, while applying the Co-Var measure and EV-complex program on
 a set of protein-protein interaction complexes, co-evolutionary pairings
 were obtained in interface and non-interface regions in protein
 complexes. The Co-Var approach involves determining high degree
 co-evolutionary pairings that include multiple co-evolutionary connections
 between particular co-evolved residue positions in one protein with
 multiple residue positions in the binding partner. Detailed analyses of
 high degree co-evolutionary pairings in protein-protein complexes involved
 in cancer metastasis suggested that most of the residue
 positions forming such co-evolutionary connections mainly
 occurred within functional domains of constituent proteins and
 substitution mutations were also common among these positions. The
 physiological relevance of these predictions suggests that Co-Var can
 predict residues that could be crucial for preserving functional
 protein-protein interactions. Finally, Co-Var web server
 (http://www.hpppi.iicb.res.in/ishi/covar/index.html) that implements this
 methodology identifies co-evolutionary pairings in
 intra and inter-protein interactions.
description: A number of protein-protein interaction complexes [100] were
 identified from previous published data (1-3) and complexes involving
 proteins with sufficient number of homologs and available crystal
 structure were selected. Around 50 protein complexes were considered as
 “positive set”. Additionally, non-interacting proteins from the Negatome
 database (4) were considered as the “negative set”. Close orthologs or
 similar sequences were determined using DELTA-BLAST (Domain enhanced
 lookup time accelerated BLAST) (5) and taxonomy filtered non-redundant
 sequences having E-value &lt;= 1E-04, query coverage &gt;= 70%,
 sequence identity &gt;= 45% were utilized for preparing multiple
 sequence alignments (MSA) representative of each sequence family in MAFFT
 (6). Alignments for homologous sequences of the representative interacting
 and non-interacting proteins in the “positive set” and the “negative set”
 were prepared in this manner. References
 Mintseris, J.
 and Weng, Z. (2003), Atomic contact vectors in protein‐protein
 recognition. Proteins, 53: 629-639. doi:10.1002/prot.10432 Sowmya, G., Breen, E. J., & Ranganathan, S. (2015). Linking structural features of protein complexes and biological function. <i>Protein science : a publication of the Protein Society</i>, <i>24</i>(9), 1486-94. Rodriguez-Rivas, J., Marsili, S., Juan, D., & Valencia, A. (2016). Conservation of coevolving protein interfaces bridges prokaryote-eukaryote homologies in the twilight zone. Proceedings of the National Academy of Sciences of the United States of America, 113(52), 15018–1502 doi:10.1073/pnas.1611861114 Smialowski, P., Pagel, P., Wong, P., Brauner, B., Dunger, I., Fobo, G., Frishman, G., Montrone, C., Rattei, T., Frishman, D., et al. (2009). The Negatome database: a reference set of non-interacting protein pairs. <i>Nucleic acids research</i>, <i>38</i>(Database issue), D540-4. Boratyn, G. M., Schäffer, A. A., Agarwala, R., Altschul, S. F., Lipman, D. J., & Madden, T. L. (2012). Domain enhanced lookup time accelerated BLAST. <i>Biology direct</i>, <i>7</i>, 12.doi:10.1186/1745-6150-7-12 Katoh K, Misawa K, Kuma K, Miyata T. MAFFT: a novel method for rapid multiple sequence alignment based on Fast Fourier transform. Nucleic Acids Res. 2002;30(14):3059–66.
description: Alignments utilised for validating the Co-Var methodology
 (“positive set” and “negative set”) are provided in the 'Validation
 Set' folder. Predicted co-evolutionary pairings and the distances
 among them for the 'Validation Set' are included in the
 'Program Outputs' folder.  Data pertaining to
 the application  case studies has been included in the 'Case
 studies' folder. Processed data utilised for
 generating the final figures corresponding to each figure is provided in
 the 'Processed data' folder. 
 <b>Availability: Co-Var</b> web server implementing
 this methodology that identifies co-evolutionary pairings in
 intra-protein, inter-protein, protein-DNA or protein-RNA complexes is
 available at http://www.hpppi.iicb.res.in/ishi/covar/index.html and the Co-Var package can be downloaded from http://www.hpppi.iicb.res.in/ishi/covar/download/covar-loc.zip.