COMPUTER SIMULATION THEORY OF GLOBULAR PROTEIN DYNAMICS

计算生物学中最重要的悬而未决的问题之一是无法根据蛋白质的氨基酸序列预测蛋白质的三维结构。在实践中，蛋白质折叠问题的解决需要同时解决两个相互关联的问题。从无数错误折叠的构象中识别自然状态的潜力部分地克服了这两个问题。一种二级和三级限制信息的方法，以将分子引导到类似原生的区域。然而，这种方法通常会产生两到三个低能量拓扑。因此，我们建议开发改进的协议来从多个序列信息预测二级结构和三级约束。此外，由于原生态拓扑的生成和截断还严重依赖于对势的无约束、经验性的贡献，这些项也必须加以改进。特别是，侧链埋藏将得到更充分的描述，局部序列比对将被用于开发更敏感的对电位。此外，一旦产生了低能拓扑，就会得到自洽的三级约束，从而产生较少扭曲的类自然构象。这应该会通过开发计算更有效的简化蛋白质采样技术以及通过开发计算更有效的简化蛋白质模型来提高对天然类蛋白质的能量选择性。为了确定该方法对三级结构预测的有效性范围，将对大量已知和未知结构的序列进行应用。对该算法的重要、独立的测试将通过参与盲目预测、竞赛，包括CASP3，通过对其他蛋白质进行盲目预测，以及通过互联网向其他研究人员传播所有软件来进行。

One of the most important unsolved problems of computational biology is the inability to predict the three-dimensional structure of a protein from its amino acid sequence. In practice, the solution to the protein folding problem demands that two interrelated problems be simultaneously addressed. Potentials that recognize the native state from the myriad of misfolded conformations partly surmounting both problems. A means of secondary and tertiary restraint information to funnel the molecule towards native-like regions. However, such approaches typically generate two to three low energy topologies. Thus, we propose to develop improved protocols to predict secondary structure and tertiary restraints from multiple sequence information. Furthermore, since native state topology generation and section is also crucially dependent on the non-restraint, empirical contributions to the potential, these terms must also be improved. In particular, side chain burial will be more adequately described and local sequence alignments will be employed to develop much more sensitive pair potentials. Furthermore, once low energy topologies are generated, self-consistent tertiary restraints will be derived so that less distorted native-like conformations will be generated. This should enhance the energetic selectivity for native-like as well as by developing computationally more efficient reduced protein sampling techniques as well as by developing computationally more efficient reduced protein models. To establish the range of validity of this approach to tertiary structure prediction, application will be made to large number of sequences of known as well as unknown structure. Significant, independent testing of this algorithm will be done by participating in blind prediction, contests, including CASP3, by making blind predictions of other proteins, and by disseminating all software to other investigators over the Internet.