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FOLDING THE SHEETS: USING COMPUTATIONAL METHODS TO PREDICT THE STRUCTURE OF PROTEINS 236 Chapter 9â Folding the Sheets: Using Computational Methods to Predict the Structure of Proteins Fred E. Cohen University of California, San Francisco In principle, the laws of physics completely determine how the linear sequence of amino acids in a protein will fold into a complex three-dimensional structure with useful biochemical properties. In practice, however, predicting structure from sequence remains a major unsolved problem. In this chapter the author outlines current approaches to structure prediction. The most fruitful approaches are not based on physical simulations of the folding process, but rather exploit the conservative nature of evolution. Using statistical methods, pattern matching techniques, and combinatorial problem solving, protein structure prediction is becoming steadily more tractable. At the crossroads of physics, chemistry, biology, and computational mathematics lies the protein folding problem: How does a linear polymer of amino acids assemble into a three-dimensional object capable of executing a precise chemical function? Implicit within this question are both kinetic and thermodynamic issues: Given a particular protein sequence, what is the conformation of the folded state? What path does the unfolded chain follow to reach this folded state? This chapter outlines the history of the protein folding problem, current research efforts, the obstacles to accurate prediction of protein structure, and the areas for future inquiries.