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

描述（由申请人提供）：提出了一项关于血浆中小分子的非酶促质子化反应的联合理论-实验研究，作为控制可质子化分子（如胺）生物活性的非特异性生物学工具。 碳酸-直到最近才被认为在这方面不重要，与乳酸一起，被认为可能是血浆中最重要的质子化剂。这与传统观点不同，传统观点认为大多数质子化反应通过与（H+）aq相互作用发生在血浆中。作为一个特别的焦点，碳酸化学将在碳酸氢盐/CO2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，计算研究将现实地捕捉液体水环境的性质，并产生现实的反应路径的酸碱质子转移。平行前沿超快光谱实验将直接测量质子化率。支持主要目标的进一步目标将是确定和更深入地理解酸碱质子转移的机制和反应速率，以及将这种根本性的重要理解应用于血浆中的碳酸和乳酸化学。该研究计划的结果将在生物学，药理学和医学的许多领域产生重要影响，例如了解数十种经证实具有生物活性的小质子化分子的生物活性，这些分子通过血液系统转移，直到它们与指定的靶点相互作用，改善药物输送。拟议的研究将导致在博尔德和BGU的前沿水平的实验和理论在一个具有高度生物物理意义的领域的几个研究生的培训。它从教科书水平的新角度解决了基本的生物物理学/生物化学思想。结果将用于博尔德和BGU的教育场所，包括博尔德的荣誉普通化学课程和生物物理课程，以及博尔德面向5-15岁儿童的科普宣传“CU奇才”系列。更一般地说，这些结果将对非常广泛的科学家社区有用，我们将在广泛覆盖的科学期刊上回顾其新颖的方面，并使其可供公众使用。!

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. !