THEORETICAL STUDIES OF PROTEIN FOLDING

该提案描述了新的计算算法的发展 以及确定蛋白质结构的潜在功能 序列和有限的结构信息。PR，消除结果 演示低分辨率(约6A)结构可以 使用简化模型获得复杂蛋白质，如肌红蛋白 如果指定了二级结构，则为 其他螺旋蛋白和一种混合的α/β蛋白也被 获得。详细的、全原子结构已经从这些 通过输入分子力学程序简化模型结构， 添加侧笔、最小化和/或模拟退火法。这个 推广静止和同事的Born连续介质溶剂模型或 用Poisson-Boltzmann方程的数值解来处理 溶剂效应。将使用量子化学反应场方法来 开发新的高分辨率势函数。 该提案的最初目标是进一步发展这一方法，以便 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，1-2A结构可以 然后在表示的分子力学水平上产生。这 然后，技术可以用来定性地扩大蛋白质的范围 易于核磁共振结构测定，减少溶解时间， 作为每个残留物的远程距离约束的数量， 所需的数量将大大减少。在更长的时间尺度上，有 发展新的实验方法的前景，涉及分子 生物学和光学光谱学，用于研究无法获得的蛋白质 核磁共振。这是一种更具投机性的努力，目前还需要新奇的东西 实验方法学的未确定进展以及改进 计算算法。 实现更有效的结构的实际目标 决心将对基础结构生物学产生相当大的影响 以及合理的药物设计努力。在更根本的层面上，研究 大量的蛋白质构象和潜在功能将 对蛋白质折叠的物理化学有了实质性的了解 以及准确描述这一点的蛋白质模型的构建 化学反应。

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.