Computer Synthesis Of Chimeric Proteins
Not long ago, the biochemist’s main tool was a chromatograph or an electrophoresis plant, but now specialists in bio-informatics use special software to simulate biochemical processes and the behaviour of complex molecules.
This approach was used to research factitious proteins of the cytochrome P450 family by researchers from the V.N. Orekhovich Research Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, guided by A.V. Lisitsa, Ph.D. (Biology), and their colleagues from Vanderbilt University (USA) guided by Doctor Larisa Podust. The project has been sponsored by Rosnauka and the CRDF foundation.
Proteins of this family play an important role in the organism: they are responsible for oxidation of xenobiotics – alien chemical compounds harmful to cells. Oxidation assists in removing xenobiotics from the organism, providing for cells’ purification from chemical skimming. The primary importance of cytochromes P450 resulted in the fact that these proteins are found practically in all existing organisms – in bacteria, plants, fungi and animals. Preserving general function universality, cytochromes P450 show great diversity in their structural organization.
The main aim is to consider various structural elements of real existing proteins as a peculiar meccano, out of which factitious chimeric proteins can be assembled to combine components of several different structures. It is assumed that chimeric proteins will be able to perform a pre-programmed biological function. Why is that needed? – The answer is simple: factitious cytochrome P450-based proteins may be used by biotechnologists for complicated chemical synthesis leading to creation of drug prototypes, agricultural chemistry preparations and many others.
The main question facing the researchers is as follows – what are the rules to “play” the meccano consisting of protein elements? “About three years ago, we set up a hypothesis that the leading role of cytochromes P450 in the structural organization and in their interaction with chemical substances is played by motives, i.e., a certain spatial configuration of individual protein fragments, typical folds and spirals of this long molecule,” says A.V. Lisitsa. “It is them that we are going to identify at the first stage of the work. Then, with the help of a PC, we shall replace some motives by others, and a three-dimensional structures calculation will allow to select such chimeric proteins, which will take the necessary spatial configuration and will be responsible for definite functions, but will not remain a senseless chain of molecules after the synthesis. And then, the neurocomputer will begin its work.”
The neurocomputer is used in bio-informatics to denote the simplified representation of the brain in the form of a virtual neurons network. Such a network is capable of accumulating information and learning. The network (by the example of experimentally known reactions of the entire spectrum of substances with cytochromes P450) learns to recognise correct interaction types. Then the network will evaluate with what substances the factitious protein built from elements of natural structures will interact. The work will be considered successful if the researchers succeed to prove that the developed method allows to forecast correctly the artificial proteins’ functions.
“Contemporary genetic engineering methods allow to produce rather easily a transgene (recombinant) organism that will synthesize computer-designed chimeric proteins,” says A.V. Lisitsa. “The preparations required for that will be produced and delivered to us by the US colleagues, and we shall clone microorganisms in Russia, purify the protein produced by it and check their activity with the help of the US reagents. If everything goes on successfully, factitious protein preparations will be sent to Vanderbilt University, where they will be crystallized, and then the structure for assessment of computor simulators accuracy will be investigated. One of Russian students will be involved in these experiments, he/she will go to the USA to acquire protein crystallography skills. The statistical model developed in the course of the research may be used for rational construction of other proteins with new or improved properties.”
Sergey Komarov | alfa
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