The Physiological Role of Carbonic Acid and Lactic Acid as Protonating Agents of

描述(由申请人提供)：建议对血浆中发生的小分子的非酶质子化反应进行联合理论和实验研究，作为一种非特定的生物工具，用于控制可质子化分子的生物活性，如胺。 碳酸-直到最近还被认为在这方面并不重要，与乳酸一起被认为是血浆中最重要的质子化试剂。这与大多数质子化反应在血浆中通过与(H)AQ相互作用而发生的传统看法不同。作为一个特别的重点，碳酸化学将在碳酸氢盐/二氧化碳缓冲液的背景下进行研究，该缓冲液确定并稳定血液pH值约为7.4。这项研究的主要目标是通过最先进的计算和实验来支持这一新图像。特别是，计算研究将真实地捕捉液体水环境的性质，并为酸碱质子转移生成真实的反应路径。平行的尖端超快光谱实验将直接测量质子化速率。支持主要目标的进一步目标将是确定和更深入地了解酸碱质子转移的机制和反应速度，并将这一根本重要的理解应用于血浆中的碳酸和乳酸化学。该研究计划的结果应该会在生物学、药理学和医学的许多领域产生重要影响，例如了解数十个已被证明具有生物活性的可质子化小分子的生物活性，直到它们与指定的目标相互作用，改善药物输送。拟议的研究将导致博尔德大学和北京国立大学的几名研究生在一个具有高度生物物理意义的领域进行前沿实验和理论方面的培训。它从教科书层面的新视角阐述了生物物理学/生物化学的基本概念。研究成果将用于博尔德和北卡罗来纳州立大学的教育场所，包括博尔德的荣誉普通化学课程和生物物理学课程，以及博尔德面向5-15岁儿童的科普推广活动“CU奇才”系列。更广泛地说，这些结果将对非常广泛的科学家社区有用，我们将在覆盖广泛的科学期刊上审查其新颖的方面，并将其提供给普通公众。好了！

DESCRIPTION (provided by applicant): A joint theoretical-experimental study is proposed of non-enzymatic protonation reactions of small molecules occurring in blood plasma, as a non-specific biological, tool for controlling the bioactivity of protonatable molecules such as amines. Carbonic acid--- until very recently thought to be unimportant in this context, together with lacti acid, are argued to be likely the most important protonating agents in the blood plasma. This differs from the conventional wisdom that most protonation reactions occur in blood plasma through interaction with (H+)aq. As a particular focus, carbonic acid chemistry will be studied in the context of the bicarbonate/CO2 buffer, which determines and stabilizes blood pH at about 7.4. The primary goal of the research is to support this new image, via state of the art computations and experiments. In particular, computational studies will realistically capture the nature of liquid aqueous environment and generate realistic reaction pathways for acid-base proton transfers. Parallel cutting edge ultrafast spectroscopy experiments will directly measure the protonation rates. Further goals supporting the primary goal wil be the determination and deeper understanding of the mechanism and reaction rate of acid-base proton transfer and application of this fundamentally important understanding to carbonic and lactic acid chemistry in blood plasma. The research program's results should have an important impact in many areas in biology, pharmacology and medicine, such as comprehending the bioactivity of scores of small protonatable molecules of proven bioactivity transferred through the blood system until they interact with their designated target, improving drug delivery. The proposed research will result in the training of several graduate students at Boulder and BGU in frontier level experiment and theory in an area of high biophysical significance. It addresses basic biophysics/biochemistry ideas from a new perspective on a textbook level. Results will be used in education venues at Boulder and BGU, including an Honors General Chemistry course and Biophysical Program courses at Boulder, and in the Boulder popular science outreach 'CU Wizards' series for children of ages 5-15. More generally, the results will be of use to a very broad community of scientists and we will review its novel aspects in broad- coverage scientific journals and make them available for the general public. !