SCIENTIFIC TESTING OF NMR STRUCTURE DETERMINATION SCHEME

描述：(改编自申请者摘要)本报告的目的 建议进行与新的核磁共振相关的科学测试 目前在Biosym开发的软件包，即集成的 用于确定分子结构的理论/计算工具 核磁共振数据。该方案结合了一种精心设计的核磁共振松弛矩阵方法 (IRMA)使用各种分子建模公式，如距离 几何(DG)、约束分子动力学(RMD)/约束能量 极小化(REM)和动态模拟退火法(DSA)。结构 确定是通过首先使用扩展的 T.Havel度量矩阵公式的一种版本，称为DG II或带有 最近提出的DSA方案，该方案已在Biosym使用 分子动力学(MD)包发现。这之后是 结构优化，使用发现集成版本的IRMA。 这一复杂系统的完整性和有效性取决于 仔细的科学测试，目的是评估局限性(一方面)和 替代组件的相对优势(另一方面)。此外， 这一系统所固有的独特的科学严谨性将充分 只有当我们能说明它的瞬时解决能力时才会感激 分子结构模棱两可。DG II和基于发现的DSA将是 以Crambin和ZnIV指状作为测试用例进行比较评估 域。这两种技术的局限性和优点将会被准确地指出。 通过对牛胰蛋白酶抑制剂(BPTI)进行详细的 调查结果，并与前人研究结果进行比较。一个 IRMA的敏感性测试将使用α-淀粉酶进行 抑制剂Tendamistat。治疗内科疾病的重要意义 动议，只要以前的结构性含糊之处能够得到解决 通过恰当地解释动态现象，将通过 中性粒细胞多肽的再研究5.本研究的价值 的技术创新和商业价值将由 科学合理、新颖、独特和非常有用的解释工具 核磁共振结构。

DESCRIPTION: (Adapted from Applicant's Abstract) The objective of this proposal is to carry out the scientific testing associated with a new NMR software package developed currently at Biosym, namely an integrated theoretical/computational tool for determining molecular structures from NMR data. The scheme combines an elaborate NMR Relaxation Matrix Approach (IRMA) with various molecular modeling formulations such as Distance Geometry (DG), Restrained Molecular Dynamics (RMD)/Restrained Energy Minimization (REM) and Dynamical Simulated Annealing (DSA). Structure determination proceeds by first `generating' a structure, with an extended version of T. Havel's metric matrix formulation called DG II or with a recently proposed DSA scheme, which has been implemented at Biosym using the molecular dynamics (MD) package DISCOVER. This is followed by structure refinement, pursued using a DISCOVER-integrated version of IRMA. The integrity and validity of this complex system is contingent upon careful scientific testing aimed at assessing limitations (on one hand) and relative advantages of alternative components (on the other). Moreover, the unique scientific rigor inherent in this system will be fully appreciated only if we can illustrate its ability to solve momentarily ambiguous molecular structures. DG II and the DISCOVER-based DSA will be evaluated comparatively using as test cases crambin and ZnIV fingerlike domain. Limitations and benefits of the two techniques will be pinpointed by subjecting bovine pancreatic trypsin inhibitor (BPTI) to a detailed investigation and comparing the results with previous studies. A sensitivity test of IRMA will be performed using the alpha-amylase inhibitor Tendamistat. The important implications of treating internal motions, to the extent that previous structural ambiguities can be resolved by properly accounted for dynamic phenomena, will be illustrated by re-investigating Neutrophil Peptide 5. The merit of this research in terms of technological innovation and commercial value will be borne out by a scientifically sound, novel, unique and very useful tool for elucidating NMR structures.