Computer Assisted Modeling Contributions of Computational Approaches to Elucidating Macromolecular Structure and Function (1987) / Chapter Skim
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1 Executive Summary
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The conceptual breakthrough that led to our present mastery of genetic control of protein synthesis was the discovery that the nucleotide sequence in nucleic acids codes for the amino acid sequence of the protein being synthesized. The Rosetta Stone of molecular genetics was the elucidation of the actual code, whereby the sequence of trimers (codons)
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In their biologically active form, they are folded upon theA-nseIves, forming complex threedimensional structures. Their shape determines their biological activity.
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The second is the prediction of biological activity from tertiary structure and related data and theory. PROTEINS Primary Structure More than 5,000 protein amino acid sequences have been reported, most of which were inferred from the DNA sequences that encode them.
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The procedure uses experimental thermodynamic data on double-strand formation In synthetic RNA oligonucleotides. A dynamic programming algorithm considers all possible base pairs in the RNA and calculates the free energies of the corresponding structures.
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Two-dimensional NMR techniques are a valuable complement to x-ray diffraction for relatively small molecules (molecular weight less than 10,000) , but for the foreseeable future, crystal structure analysis will be the principal experimental source of structural data for enzymes, nucleic acid binding proteins, antibodies, and other proteins involved in the immune response or intercellular communication.
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Computers play an essential role in most of these steps. The availability of new instrumentation that allows crystallographers to produce in a few days data that previously took weeks or months of labor-intensive work is revolutionizing protein crystallography at an opportune time.
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Such methods take far more computer time and may become practical only on supercomputers. Some efforts are underway to use semiautomated pattern recognition and expert system strategies to determine threedimensional structure, but these will require substantial investments in programming and computer hardware.
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TERTIARY STRUCTURE FROM THEORY Energy Optimization According to the thermodynamic hypothesis, the amino acid sequence of a protein determines its three-dimensional structure in a given medium as the thermodynamically most stable structure. To identify this structure requires some kind of optimization strategy, which, in turn, requires procedures to generate arbitrary three-dimensional conformations of a polypeptide chain, compute the free energy of the system for each conformation, and then alter the conformation so that it ultimately corresponds to the global minimum of the free energy.
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Molecular dynamics simulation allows us to estimate theoretical mean atomic positions and deviations from the mean; rates of motion and conformation change; and ensemble averages, including thermodynamic functions such as energy, enthalpy, specific heat, and free energy. Although simple in concept, molecular dynamics simulations were not practical until the advent of high-speed computers.
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Making additional computer time available to those working in the field will help in the development/application of more detailed forcefields, produce longer simulations, encourage the simulation of larger systems that pose new physical and biological questions, and promote the application of new, more time-consuming dynamics methods to be used to ask different questions about the system. Molecular dynamics simulations show considerable promise of being able to more accurately depict the structures that are proposed on the basis of incomplete information, particularly from two-dimensional NMR.
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Beyond the need for adequate computer time, two other needs must be met. One is the need for better forcefields, particularly for nucleic acids and carbohydrates; the second is the need for improved molecular dynamic techniques designed to overcome some of the intrinsic imperfections of existing forcefields.
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compounds. The evident rapid progress in the ability to describe the environmental aspects of biopolymer systems justifies our optimism that this element of biomolecular modeling will not impede development of useful predictive methods.
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Two types of computer hardware are necessary: high speed color graphics and affordable but powerful minicomputers dedicated to modeling. Data on the three-dimensional structure of proteins are becoming available at an increasing rate as we improve our understanding of some of the relationships between structure and function of proteins.
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The current state of knowIedge does not indicate that a single DNA sequence determines the primary structure of the complex carbohydrate. It is not yet possible to predict the primary structures of complex carbohydrates from DNA sequences, and the three-dimensional structures of glycoproteins, glycosphingolipids, and other complex carbohydrate-containing molecules can never be completely predicted without analyzing the two-dimensional structures of the carbohydrates.
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The interplay of theory and experiment results in the increasing refinement of the theory-based models, which in turn can be used to predict the behavior and properties of the actual molecules. Availability of computer software and access to computer time and computer-based data banks are often the factors that limit the rate of progress in structural biology.
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The areas requiring attention include the need for readily available data banks of protein and nucleic acid sequences as well as model-derived structures; improved capability of and access to supercomputers; provisions of educational opportunities in the area; and use of the most appropriate physical and intellectual resources for the performance of research. Our recommendations for dealing with these issues are cleta~led in Chapter 10 and summarized in the following section.
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Several mechanisms are available, such as expanding graduate programs through new training grants; increased graduate fellowship and postdoctoral fellow programs; workshops, including formal hands-on training programs in molecular dynamics and molecular graphics; and working meetings of independent investigators to address critical limiting aspects of a particular problem.
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