THEORETICAL STUDIES OF PROTEIN FOLDING

这一建议描述了新的计算算法的发展 和潜在的功能，以确定蛋白质结构， 序列和有限的结构信息。Pr，消除结果 证明低分辨率（约6A）结构可以 对于复杂的蛋白质如肌红蛋白，使用简化模型获得 如果指定了二级结构，则为蛋白质的; 其它螺旋蛋白和一种混合的α/β蛋白也已被 得到了详细的，全原子结构已经从这些产生 通过输入到分子力学程序中来简化模型结构， 添加侧链以及最小化和/或模拟退火。的 推广了Still及其同事的Born连续介质模型， Poisson-Boltzmann方程的数值解被用来处理 溶剂效应量子化学反应场方法将用于 开发新的高分辨率势函数。 该提案的初步目标是进一步发展这一方法， 在给定二级结构的情况下，可以可靠地获得3-4A结构 对于来自简化模型的任意蛋白质，1-2 A结构可以 然后在分子力学的表示水平上产生。这 然后，技术可以用于定性地扩展蛋白质的范围， 易于NMR结构测定并减少溶解时间， 作为每个残基的长范围距离约束的数量， 所需的将大大减少。在较长的时间尺度上， 发展新的实验方法的前景，包括分子 生物学和光学光谱学，用于研究蛋白质， 匪r这是一个更投机的奋进，将需要新颖的， 在实验方法上的进展以及改进 计算算法 实现更有效结构的实际目标 测定将对基础结构生物学产生重大影响 以及合理的药物设计工作。在更基本的层面上，研究 大量的蛋白质构象和潜在的功能将 对蛋白质折叠的物理化学有了实质性的了解 以及蛋白质模型的构建， 化学.

This proposal describes the development of new computational algorithms and potential functions for determining protein structure from the sequence and limited structural information. Pr,eliminary results demonstrate that low resolution (approximately 6A ) structures can be obtained for a complicated protein such as myoglobin using a reduced model of the protein if secondary structure is specified; results for several other helical proteins and one mixed alpha/beta protein have also been obtained. Detailed, all-atom structures have been generated from these reduced model structures via input into a molecular mechanics program, addition of side chalns, and minimization and/or simulated annealing. The generalize Born continuum solvent model of Still and coworkers or numerical solution of the Poisson-Boltzmann equation is used to treat solvent effects. Quantum chemical reaction field methods will be used to develop new high resolution potential functions. The initial goal of the proposal is to further develop this methodology so that, given secondary structure, 3-4A structures can reliably be obtained for an arbitrary protein from the reduced model, and 1-2 A structures can then be generated at the molecular mechanics level of representation. This technology can then be used to qualitatively extend the range of proteins amenable to,NMR structure determination and reduce the time to solution, as the number of long range distance constraints per residue that are required will be diminished considerably. On a longer timescale, there are prospects for developing new experimental methods, involving molecular biology and optical spectroscopy, for studying proteins inaccessible to NMR. This is a more speculative endeavor and will require novel, as yet undetermined advances in experimental methodology as well as improved computational algorithms. Achievement of the practical goals of more effective structure determination will have considerable impact on basic structural biology and on rational drug design efforts. On a more fundamental level, studies of a large number of protein conformations and potential functions will yield substantial insight into the physical chemistry of protein folding and the construction of protein models which accurately describe this chemistry.