ROAMING: SOLUTION STRUCTURE OF PNA AND DNA DOUBLE-HELICES WITH AND WITHOUT META

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本方案由两个项目组成：项目1.PNA解决方案结构。该方案的目的是表征不同金属取代的PNA/PNA和DNA/DNA双螺旋在溶液中的结构和动力学。所获得的结构将被用作半经验和从头算电子转移(ET)研究的输入，以研究序列、结构、柔性、溶剂和电荷对ET的影响。我们的长期目标是设计和合成基于金属-肽核酸(金属-PNA)双链的分子系统，这使得电子流动能够得到精确的控制。这个项目是与Catalina Achim教授的卓有成效的合作，他合成了含有金属的PNA，David Waldeck教授和Eric Borguet教授进行了电子转移实验，David Beratan教授将使用从头算和半经验方法来计算电子转移速率。项目2.突变的RT-NNRTI复合体。我们HIV-1逆转录酶(RT)研究的长期目标是设计新的抗艾滋病药物，更有效地对抗野生型和突变型RT。我们最近完成了一项关于几种药物(包括最新一代、更有效的DAPY)在野生型RT结合口袋中的相互作用的研究(如进度报告所述)。为了对这些药物提出修改建议，我们需要确保我们的结论在突变RT存在的情况下也是有效的。因此，拟议的修改应该对野生型和常见突变都有效。这项研究的目的是了解突变的RT Lys103Asn之间的相互作用。建议的药物衍生物将在我们的合作者Brin教授的实验室合成。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This proposal consists of two projects: Project 1. PNA solution structure. The objectives of this proposal are to characterize the structure and dynamics of PNA/PNA and DNA/DNA double helices in solution, with different metal substitutions. The obtained structures will be used as input to semi-empirical and ab initio electron transfer (ET) studies, in order to study the effect of sequence, structure, flexibility, solvent and charge on ET. Our long-term goal is to design and synthesize molecular systems based on metal-peptide nucleic acids (metal-PNA) duplexes, which allow the precise control of electronic flow. This project is a fruitful collaboration with Prof. Catalina Achim, who synthesizes metal-containing PNA, Prof. David Waldeck and Eric Borguet, who conduct electron transfer experiments, and Prof. David Beratan, who will use ab-initio and semi-empirical methods to calculate electron transfer rates. Project 2. Mutant RT-NNRTI complexes. The long term goal of our HIV-1 reverse transcriptase (RT) research is to design new anti-AIDS drugs, more effective against wild-type and mutant RT. We have recently completed a study of the interactions of several drugs (including the latest generation, more effective, DAPYs) in the binding pocket of wild-type RT (as detailed in the Progress Report). In order to propose modifications to these drugs, we need to ensure that our conclusions are also valid in the presence of mutant RT. The proposed modifications should, then, be effective against both wild-type and commonly occurring mutations. The objectives of the proposed research are to understand the interactions with mutant RT Lys103Asn. The proposed drug derivatives will be synthesized in the laboratory of our collaborator, Prof. Brin.