Computational Structural Biology Lab

Department of Biotechnology
Indian Institute of Technology Kharagpur

Biographical Background of Dr. Ranjit P. Bahadur

With a Bachelor degree in Physics and Master degree in Electronics from University of Calcutta, Dr. Bahadur joined at the Department of Biochemistry, Bose Institute, as a PhD student in Bioinformatics program. Training in Electronics, Physics, Chemistry and Mathematics during undergraduate and postgraduate studies helped him to tackle the problems in the interdisciplinary field of Bioinformatics and Computational Biology. He also possesses a post graduate diploma in computer science which immensely helped to develop many computational tools to inspect the basic mechanism behind a biological phenomenon. The main focus of his doctorate thesis was to understand the structural basis of macromolecular nteractions, mainly focusing on protein-protein interactions. He was also interested to know how a protein folds. Curiosity to know in detail helped him to develop many ideas to solve different problems in this field. During the post doctoral period he studied many new systems like how proteins are assembled to build a capsid in viruses; how does a protein specifically recognize a RNA molecule, and dynamics behavior of the biomolecules in the cellular environment.

Discriminating the specific and non-specific protein-protein interactions

It is well established that specific recognition of the macromolecules is a rule rather than exception, and non-specific interactions can lead to disease. Many of the cellular processes are controlled by the binary protein-protein interactions, where the specific recognition of two polypeptide chains is crucial, but the understanding over the origin of the specificity is poor. These binary complexes can be divided into two major categories: homodimers, where the polypeptide chains have similar sequence and their a ssociation is coupled with the folding process; and the hetero-complexes, where two independent folded polypeptide chains interact to carry out a definite cellular function. These interactions are specific and are highly selective in nature. Another kind of protein-protein interaction occurs in the crystal lattice when the supersaturated solution of a protein crystallizes. They are non-specific and do not have any biological selection, and often difficult to identify in crystalline state. To understand the origin of affinity and specificity of these interactions, physicochemical and structural properties of the protein-protein interfaces of these complexes have been analyzed. Based on this analysis a novel algorithm has been developed to discriminate the specific from the non-specific interactions in a given protein crystal.
  1. Proteins 2003; 53:708-719.
  2. J. Mol. Biol. 2004; 336:943-955.
  3. Proteins 2005; 60:36-45.
  4. J. Proteome Res. 2005; 4:1600-1609.
  5. BMC Structural Biology 2006; 6:11, 1-5.
  6. Protein Sci. 2006; 15: 2082-2092.
  7. Quart. Rev. Biophys. 2008; 41:133-180.

Elucidation on the assembly of large macromolecules

Besides binary complexes, cells contain macromolecular machines, which often play indispensable role in many biological processes. The best representative examples of such kind of macromolecular assemblies are the capsids of icosahedral viruses. They are made up by hundreds of protein subunits that encapsulate and protect the viral genome, and are responsible for the infections in host cells. Analysis shows that, unlike binary complexes, in viral capsids, each protein chain participates in many pairwise contacts simultaneously, and form interfaces that greatly differ in size: the larger resembles subunit interfaces in homodimeric proteins, and the smaller, packing contacts in protein crystals. Sequence conservation during evolution shows that the interface residues which are in contact with more than one interface are better conserved than the others. This analysis gives an insight into the nature of protein-protein interaction network in multi-molecular system, and explains the mechanism of the self-assembly process of viral capsids. This work could help to give a structural basis to the function and self-assembly of large cellular machines in the context of a major initiative taken by the structural genomics projects.
  1. J. Mol. Biol. 2007; 367: 574-590.
  2. Proteins 2008; 71:407-414.

Protein folding and Prediction of structures

Plant disease resistance (R) genes, the key players of innate immunity system in plants encode "R" proteins. "R" protein recognizes product of avirulance gene from the pathogen and activate downstream signaling responses leading to disease resistance. Three dimensional structure of a disease resistance gene homolog encoding resistance protein in Vigna Mungo was developed using comparative modeling to explain the mechanism of disease resistance in plant-pathogen interactopns. It was the first report of any 3D structure of "R" protein.
From the analysis of known 3D proteins structures deposited in the Protein Data Bank, a scoring function has been developed based on the residue packing in protein structures to identify the near native fold from the misfolded decoys corresponding to a given amino acid sequence. This scoring function is useful in the threading applications.
  1. J. Biomol. Struct. Dyn. 2006; 24: 123-130.
  2. BMC Structural Biology 2009; 9:76-84.

Specificity of protein-RNA recognition and prediction of the protein-RNA complexes

Protein and RNA often interacts in the cellular environment, and forms binary complexes to perform essential cellular functions. The analysis of the known structures of protein-RNA complexes helps us to understand how the protein surface specifically recognizes a RNA molecule, and developed a knowledge-based potential energy function to quantify the specificity of protein-RNA recognition, which allows rapid docking minimization and systematic searches for predicting possible protein-RNA complex structures.
  1. Nuc. Acids. Res. 2008; 36:2705-2716.
  2. Cellular and Molecular Bioengineering. 2008; 1:327-338.

RNA folding and the dynamics of complex formation

Molecular Dynamics Simulations can be used to study the dynamic behavior of the folding and interactions of macromolecules. Binding of N-protein with the boxB RNA helps to trigger the antitermination of transcription process in bacteria. The mechanism of binding and structure formation of this small protein-RNA complex have been explored by studying the energetics of the dynamics pathway of the reaction coordinate.
  1. Biophys. J. 2009; 97:3139-3149.