Multi-faceted modular interactions in proteins

Abstract

All living systems are composed of plethora of biomolecules. There are various types of biomolecules such as proteins, DNA, RNA, carbohydrates and metabolites. All the reactions in a biological system involve interactions between these biomolecules. Interestingly as well as intriguingly, these simple yet strong chemical interactions between biomolecules drive all the forms of life. Importance of these interactions can be realised from the numerous disease states associated with the impairment of these interactions. The interactions involving proteins have been studied in this thesis. Proteins more than often consist of more than one module (protein domains). Many protein domains can evolve, function, and fold independently of other domains in a protein. During the functional lifetime of a protein domain, it can interact with other protein domains that are part of the same protein or part of another protein, small molecules, DNA, etc. These interactions bring about the multi-functionality of the protein. When proteins interact with different molecules, it can use overlapping or different regions to interact. Here, we have studied the intricacies of such interactions, and applied the learning for the development of lead molecules. To this end, detailed analyses have been carried on a large-scale dataset of all known protein–protein complexes in Protein Data Bank (PDB) and BioGRID resources to understand the fold space of protein assemblies (Chapter 2); modular interactions between protein domains in multi-domain proteins (Chapter 3); features defining the promiscuity and specificity of proteinases and proteinases inhibitors (Chapter 4); design of peptide binders at the protein-protein interface (Chapter 5), and identification of ligands which can interact with multiple conformations of Lck kinase (Chapter 6).