Applications of Computers in Biology
Since the Applications of computers in biology completion of the Human Genome Project, biology is undergoing a total change in philosophy and paradi and a "New Biology" is being born. Biology is now being complemented by and rests heavily on information technologies and bioinformatics in particular. We now understand how faulty genes play a role in diseases. With this knowledge, the commercial sector is shifting away from diagnostics and toward developing a new generation of therapeutics based on genes. Drug design is being revolutionized as researchers create new classes of medicines based on the use of information on gene sequence and protein structure function, rather than the traditional trial and-error method. computational studies of the protein folding problem, determination of the interaction sites of proteins. the drug design problem and the experimental verification of computational findings by in vitro experiments are among the fields of interest.
Computational prediction of protein structure and function:
The completion of the Human Genome Project created a major breakthrough in our understanding of biological systems in general and made a great impact on medicine and engineering. Most importantly it showed that there are thousands of proteins whose three dimensional native structures are not yet known. Knowledge of the three dimensional structure of a protein is essential for understanding its function and its interactions with molecules such as drug molecules. The three dimensional structure of a protein may be determined by experiments or by computational techniques. Experiments are time consuming and costly. Additionally, for many proteins it is difficult to determine structure experimentally. Therefore, there is strong emphasis on computational techniques. Computationally, the native structure of a protein may be predicted either by techniques such as molecular dynamics or by using bioinformatics tools . Both techniques are being employed in our laboratories. The knowledge of the dynamics of folding is also important, because several types of cancers, as well as Alzheimer's, Parkinson's disease etc., result from anomalies during the folding process. The dynamics of protein folding is also being investigated in our laboratories. Along with folding. prediction of interaction sites between proteins is essential. In one area of research we predicted the three dimensional structure of a protein called cryptochrome. Cryptochrome plays a major role in biological clock and regulates the biological activity of many organisms. The duration of biological activity varies widely from one organism to another for several essential biological processes
The completion of the Human Genome Project created a major breakthrough in our understanding of biological systems in general and made a great impact on medicine and engineering. Most importantly it showed that there are thousands of proteins whose three dimensional native structures are not yet known. Knowledge of the three dimensional structure of a protein is essential for understanding its function and its interactions with molecules such as drug molecules. The three dimensional structure of a protein may be determined by experiments or by computational techniques. Experiments are time consuming and costly. Additionally, for many proteins it is difficult to determine structure experimentally. Therefore, there is strong emphasis on computational techniques. Computationally, the native structure of a protein may be predicted either by techniques such as molecular dynamics or by using bioinformatics tools . Both techniques are being employed in our laboratories. The knowledge of the dynamics of folding is also important, because several types of cancers, as well as Alzheimer's, Parkinson's disease etc., result from anomalies during the folding process. The dynamics of protein folding is also being investigated in our laboratories. Along with folding. prediction of interaction sites between proteins is essential. In one area of research we predicted the three dimensional structure of a protein called cryptochrome. Cryptochrome plays a major role in biological clock and regulates the biological activity of many organisms. The duration of biological activity varies widely from one organism to another for several essential biological processes
Our algorithm principally seeks pairs of proteins that may interact in a dataset of protein structures (target dataset) by comparing them with a dataset of interfaces (template dataset) which is a structurally and evolutionarily representative subset of biological and crystal interactions present in the Protein Data Bank (PDB).
PRISM consists of a web interface to the dataset of interfaces and target structures including a summary of the proteins to which the interface belongs to (with cross-references to other biological databases where available). Computational drug design: Diseases in biological organisms are caused by failure of a protein which is a product of a particular gene in performing its function in general. Biological and chemical activities of organisms can be regulated by introducing a drug to the biological system that will target the protein responsible for the particular disease of interest. The regulation of the biological system is established when a drug molecule interacts with the active site of the target protein. The objective in drug design is to find a suitable molecule that will bind to the active site of the protein strongly for the regulation of biological and chemical activities.
The drug design problem has been addressed by experimental and computational methods. The main difficulties with experimental methods include: small number of available chemical substances for testing, high experiment costs, and the possibility that the chemical substance may be interacting with other proteins. Computational design of drug molecules is very attractive due to limitations of experimental methods.
Computational drug design involves finding the molecular structures that will create a strong interaction with the active site of the target protein. We have been working on the design of drugs for treating Chronic Myeloid Leukemia (CML).
The main cause of CML is the overproduction of the abnormal fusion protein Ber-Abl which is coded by the BCR ABL oncogene. The production of BerAbl protein can be regulated by Gleevec which is proven to be very effective at the early stages of CML. Gleevec is not effective at later stages of CML due to mutation. We conducted computational experiments to modify Gleevec in order to obtain mutation resistant drugs. Our computational analysis resulted in several drug candidates that may be more effective than Gleevec .
As can be seen from the above examples, computational studies in biology make it possible to detect the rules of protein structure function relations and protein-protein interactions. These will certainly speed up the drug design. Outcome of the research at our Center will help in developing new drugs against biological clock related diseases as well as understanding the principles of Understanding structure-function of cryptochrome will enable us to develop drugs against clock related diseases At the present the three dimensional structure of cryptochrome cannot be determined experimentally, and computational techniques sccms to be the only alternative.
