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Protein motions can provide clues of their functional roles, say IISc scientists

It is said that our body houses over 25000 different proteins. If we consider the body as a huge factory of sorts, then proteins are like the workers in it; they deal with security, communication, transportation, structural stability, maintenance, and every other role that one can envision. But unlike actual human workers, proteins are molecules, made up of units called amino acids-imagine a long chain of beads (amino acids) of different sizes and shapes strung together; protein sequences are just permutations and combinations of 20 different amino acids. 

Professor Srinivasan and his team at the Molecular Biophysics Unit, IISc, Bangalore, are most interested in studying the interrelation between protein sequences, their structures, and their functions. It is the amino acid chains of proteins that fold upon themselves, to give a final 3D conformation that each protein molecule adopts. Except, of course these 3D conformations are not constant. Proteins molecules are in perpetual motion, which includes fluctuations in atomic positions, segmental motions and rigid body movement of compact sub-modules. During these dynamics when different proteins bump into each other, they 'talk'. And when they 'talk', they function. Needless to say, protein dynamics and their structural fluctuations are of a much greater consequence than was realized, opening up a whole new dimension to understanding protein biology.

In a recent study under the purview of Indo-French collaborative grant (CEFIPRA) with Dr. Alexandre G. de Brevern (INSERM, Paris), Ms. Kalaivani Raju, a student in Professor Srinivasan's lab, compared structural fluctuations across a class of proteins called Protein Kinases. Protein Kinases are essentially enzymes involved in communication; sensing and responding to signals. Many diseases including cancers have been attributed to erroneous functioning of specific kinase molecules. Kalaivani used a computational approach, wherein instead of applying the traditional and expensive method of Molecular Dynamics Simulations, she used a tool called Normal Mode Analysis (NMA) to study structural fluctuations in Protein Kinases. NMA allows one to predict the inherent mobility associated with each part of a protein and also compare the kinds of motions between different types of proteins. It was observed that functionally similar and related protein kinases have a conserved inherent motion- meaning that they tend to move in the same way. However, she also found that small regions within the related Protein Kinases displayed unique motion patterns, different from one another and these regions were involved in specific protein interactions, responsible for specific functions.

"One of the best applications of this (study) is in drug designing," says Kalaivani. Commonly, when trying to create a new drug, chemists try and design drugs that bind to aberrant protein kinases thus curbing their deviant behaviour. But many a times, it is observed that the drug also interacts with unintended proteins, causing severe side effects. How is it that a drug designed to bind to a specific unique sequence of amino acids, ends up interacting with a whole bunch of unintended molecules? The answer lies in structural conformations. Local structures even in un-related proteins can appear similar to drug targets, causing unintended side effects.

"It's like a jigsaw puzzle," explains Kalaivani, "although, a number of pieces can physically fit into a given spot, the picture is made perfect only when the correct piece is placed in its spot. Using the NMA tool one can look for regions on the target protein showing a unique pattern of mobility and confidently begin with designing drugs that uniquely interact only with desired target."

About the authors

1] Kalaivani Raju is a Ph.D. student in the Molecular Biophysics Unit, Indian Institute of Science.


2] Dr. Alexandre G. de Brevern is aPrincipal Investigator at the French National Institute of Health and Medical Research (INSERM

3] Dr. N. Srinivasanis a Professor in the Molecular Biophysics Unit, Indian Institute of Science.


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About the paper

Title:  Conservation of structural fluctuations in homologous protein kinases and its implications on functional sites

Publication: Proteins: Structure, Function, and Bioinformatics