Multi-scale Simulations of Bronic Acids in Prteasome Inhibition and Saccharide

这位候选人在亨利的指导下从佐治亚大学获得了化学博士学位 F·谢弗，格雷厄姆-珀杜化学教授。在研究生院期间进行的研究集中在 量子力学(QM)方法在确定热力学、光谱和 硅铝络合物的结构性质。这项研究生工作导致了高度的 在特定的分子系统中使用准确的方法，并一直持续到博士后培训。这个 候选人的博士后工作进一步将他在质量管理计算方面的专业知识扩展到了含硼 由于其独特的化学特性而依赖于特定方法的分子。 拟议的计算将以候选人在质量管理方法方面的背景为基础，并提供新的 具有研究大分子物质的方法经验。研究计划将调查化学 控制基于硼酸(BA)的蛋白酶体抑制和糖感觉。硼酸有 作为重要的化学结构出现在许多潜在的医疗和生物应用中。 与这些领域相关的化学相互作用将被研究如下：混合量子 机械/分子力学(QM/MM)方法与反应路径的数学建模 通过CHARMM软件套装程序中实现的新的多刻度界面访问。这些 方法代表了候选人的一个新的研究领域，并将极大地拓宽他的专长。 具体地说，这些计算将研究基于BA的蛋白酶体抑制。尽管他们在 在治疗无数癌症的过程中，这种抑制作用并不完全清楚。此外，还有一个 FDA批准的唯一蛋白酶体抑制剂Bortezoniib(二肽基-硼酸)的化疗耐药性增加 酸)。确定这种增加的阻力的原因以及结合中BAs的化学作用 Pocket将为未来的蛋白酶体抑制剂提供有价值的见解。造成这种抵抗的三个可能原因 将会被探索。这些包括：(1)了解波特佐米代谢的化学反应，(2) 通过结合疗法产生的不良反应，这些补充剂氧化了博替佐米，以及(3)潜在的 谷胱甘肽亚精胺合成酶的抑制可能会导致谷胱甘肽的增加，这是一种已知的 抵抗抑制共轭的目标。 硼酸也被证明是糖的极好的合成荧光标记物。这 Proposal还计划使用QM/MM方法来了解硼酸-糖的化学相互作用 试图以模块化的方式开发糖特定的传感器。结果将用于 设计合成受体来识别代表疾病的糖链中的糖单位 各州。 职业发展奖将帮助候选人掌握这些学习所需的工具 通过在NLH/NHLB1计算生物学实验室的继续培训。前博士后 研究重点是高精度计算较小的硼酸模型的化学性质 仅使用QM方法的系统。该奖项将促进向多长度标尺(多长度标尺)的过渡 规模)使用反应途径技术的QM/MM建模目前不在候选人的技能范围内。多个- 规模模拟代表了一个非常重要的新研究领域，它连接了许多计算学科。 这一奖项将有助于使候选人成为这一新领域的领导者。额外的实践经验将 包括通过计算机编程修改复杂计算机程序CHARMM的能力。在……里面 除了是一个全面的生物建模平台外，CHARMM还充当 计算生物学和化学领域的最新算法。候选人将获得有价值的东西 在获奖期间改进和改进反应路径方法的经验。 除了研究培训，在获奖期间的继续教育将包括参加赠款的撰写 通过校内培训和教育办公室(OITE)提供以生物学为重点的讲习班和课程 在国立卫生研究院。候选人咨询委员会将每年举行会议，讨论进展情况，并确保 达到了提出的目标，在需要的地方提出了建议。与候选人的每周会议 Mentor也将是无价的。这种支持将使候选人保持在成功过渡到 独立研究岗位。

The candidate earned a Ph.D. in chemistry from the University of Georgia working under the direction of Henry F. Schaefer, Graham-Perdue Professor of Chemistry. Research performed during graduate school focused on the application of quantum mechanical (QM) methods to determine thermodynamic, spectroscopic, and structural properties of silicon and aluminum complexes. This graduate work led to the identification of highly accurate methods for use in specific molecular systems and has continued through post-doctoral training. The candidate's post-doctoral work has further extended his expertise in QM computations to boron containing molecules that rely on specific approaches due to their unique chemistry. The proposed computations will build on the candidate's background in QM methodology and provide new experience in methods to study larger macromolecules. The Research Plan will investigate the chemistry governing boronic acid (BA) based proteasome inhibition and saccharide sensing. Boronic acids have emerged as important chemical structures for use in a number of potential medical and biological applications. Chemical interactions related to these fields will be studied with the following: Mixed Quantum Mechanical/Molecular Mechanical (QM/MM) methods and mathematical modeling of reaction pathways accessed via the new Multi-Scale interface implemented in the CHARMM software suite of programs. These methods represent a new field of study for the candidate and will broaden his expertise significantly. Specifically, these computations will investigate BA based inhibition of proteasomes. Despite their promise in the treatment of a myriad of cancers, this inhibitory effect is not fully understood. Furthermore, there is an increase in chemoresistance of the only FDA approved proteasome inhibitor, Bortezoniib (a dipeptidyl-boronic acid). Determining the cause of this increased resistance and the chemical interactions of BAs in the binding pocket will provide valuable insight for future proteasome inhibitors. Three possible reasons for this resistance will be explored. These include: (1) understanding the chemical reactions for the metabolism of bortezomib, (2) adverse reactions through conjugation therapy from supplements that oxidize bortezomib, and (3) the potential inhibition of glutathionyl spermidine synthase that may potentially cause an increase in glutathione, a known target of resistance suppressing conjugates. Boronic acids have also been shown to be excellent synthetic fluorescent markers for saccharides. This proposal also plans to use QM/MM methods to understand the chemical interactions of boronic acid-sugar complexes in an attempt to develop saccharide specific sensors in a modular fashion. Results will be used to design synthetic receptors for the identification of sugar units in glycans that are representative of disease states. The Career Development Award will aid the candidate in mastering the necessary tools for these studies through continued training in the Laboratory of Computational Biology within the NlH/NHLBl. Previous postdoctoral research focused on highly accurate computation of chemical properties of smaller boronic acid model systems using QM only approaches. This award will facilitate a transition into multiple length scale (Multi- Scale) QM/MM modeling using reaction pathway techniques not currently in the candidate's repertoire. Multi- Scale simulations represent a highly significant, new area of study that bridge many computational disciplines. This award will help to establish the candidate as a leader in this new field. Additional practical experience will include the ability to modify, through computer programming, the complex computer program CHARMM. In addition to being a comprehensive biological modeling platform, CHARMM also serves as a repository for the newest algorithms in the field of computational biology and chemistry. The candidate will gain valuable experience by refining and advancing reaction path methodology during the award period. In addition to research training, further education during the award period will consist of attending grant-writing workshops and biology focused classes offered through the Office of Intramural Training and Education (OITE) at the NIH. The candidates Advisory Committee will meet annually to discuss progress and to ensure that the proposed goals are met, making recommendations where needed. Weekly meetings with the candidate's mentor will also be invaluable. This support will keep the candidate on track to successfully transition to an independent research position.