Prasad, B.V.L.S. - PACS: A novel methodology and graphical representation for understanding protein structure from an engineer's perspective

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Title: PACS: A novel methodology and graphical representation for understanding protein structure from an engineer's perspective	P123
Prasad, B.V.L.S. shiva@mbu.iisc.ernet.in Indian Institute of Science

Despite the availability of voluminous literature and huge structural knowledge base on biomacromolecules in general and proteins in particular, a) it is still unclear, in its entirety, how a protein attains its native architecture essential for its predefined function b) therefore, rational design of proteins, peptides or drugs is not yet possible c) protein folding problem persists. Consequently, the long standing desire of biologists to reach the stage of designing a "customized protein" a de novo designed protein with a predetermined function and not predefined, finally leading to nano-biotechnology revolution for social benefits, is still an unrealized dream.
The recent discoveries and successful elucidation of natural nanomachine systems such as T4 bacteriophage structure and large bio-macromolecular assemblages such as ribosomes, ATPase rotary motors, bacterial flagellar motors and actin-myosin translation system provide hope that protein designing principles can be understood. These discoveries suggest that the architecture of the cell and the macromolecules is more important in the coordination, cooperation, assembly and function than their chemical compostion. Further, these natural nanomachine systems are being successfully described, analyzed and comprehended in terms of mechanical engineering principles. For example, microscopic bacterial flagella and flagellar motors are considered equivalent to macroscopic motors and drive shafts, whose function is to turn the shaft and trasmit torque, respectively. This suggests that engineering principles of mechanical component design might be adapted to biological macromolecular structure analysis. A protein or a group of proteins form a functional subunit. Similarly, a group of subunits, forming components coordinate to form a complex assemblage. It is apparent that proteins and DNA/RNA molecules are similar to the mechanical components of a well designed macroscopic machine system.
It is relatively easy to identify components of complex protein assemblages. However, does such a component system exist with in a single protein molecule? Is protein a biological IC (Irreducible Complex) or can a single protein molecule be further divided into different architectural components, despite its continuous chain? In this poster, an attempt is made to answer this question. Using reverse engineering principles, a novel methodology is developed to systematically identify the architectural components of aspartic proteinases. Using this methodology the entry, optimal positioning of substrate, the exit of cleaved products and the functional role played by different parts of the structure is understood with greater clarity and newer insights. It has provided plausible hints for the difference in the hydrolysis of short and long substrates. Through this methodology it is noticed that proteins are tensegrity structures, where the architectural components are equivalent of the compressional elements and the linkers between these architectural components are the tensile elements. The method can be extended to other protein families which would result in better understanding of the underlying principles of protein design. The methodology is expected to aid in understanding protein folding problem, de novo drug and protein designing. A novel visual representation is developed to graphically illustrate the methodology which associates functional relevance to the structural elements.

[1] Drexler, K.E. Molecular Engineering: An Approach to the development of general capabilities for molecular manipulation. Proc. Nat. Acad. Sci. 78, 5275-5278 (1981).
[2] Shuji Kanamaru, Petr G. Leiman, Victor A. Kostyuchenko, Paul R. Chipman, Vadim V. Mesyanzhinov, Fumio Arisaka & Michael G. Rossmann. Structure of the cell-puncturing device of bacteriophage T4. Nature. 415, 553 ? 557 (2002).
[3] Yonath, A. The Ribosome: A molecular machine with brains. Chemistry in Israel. 9, 4-12 (2002).
[4] Noji, H., Yasuda, R., Yoshida, M. & Kinosita, K. Jr. Direct observation of the rotation of F1-ATPase. Nature. 386, 299-302 (1997).
[5] Schuster, S. C. & Khan, S. The Bacterial Flagellar Motor. Annual Review of Biophysics and Biomolecular Structure. 23, 509-539 (1994).
[6] Howard, J. Mechanics of motor proteins and the cytoskeleton. (Sinauer Assoc, Sunderland; February, 2001).
[7] Ingber, D.E. The Architecture of Life. Sci. Am. 278, 48 - 57 (1998).
[8] Behe, M.J. Darwin's Black Box. (The Free Press, New York; August, 1996).
[9] Katheryn A. Ingle. Reverse Engineering. (McGraw-Hill Professional Publishing, London; 1994).
[10] David R. Davies.The structure and function of the aspartic proteinase. Annu. Rev. Biophys. Biophys. Chem. 19,189 - 215 (1990).