CAREER: Development of Non-Additive Lipid Force Fields and Application to the Study of Charged Amino Acid Residues in Lipid Bilayers and the Role of Bilayer-Resident Water

有智力价值的活细胞有内部和外部，由称为细胞膜的屏障隔开，主要由称为脂质的基本单位组成。在水中快乐(能量稳定)的分子(如盐、离子、极性分子)在膜状环境中并不总是快乐。然而，令人惊讶的是，在膜中发现了许多亲水分子，或者已知很容易穿过膜环境。观察到细胞穿透肽很容易进入细胞。由于亲水分子似乎驻留在细胞膜内并通过细胞膜进行转移，因此很自然地认为水会伴随着这一过程。水在这些过程中扮演着重要的角色。由于实验室实验不可能看到单个水分子，因此将使用计算机程序进行众所周知的分子模拟。这些计算方法结合了对生物分子如何相互作用的物理描述，跟踪单个分子在时间和空间中的运动。这使得研究人员能够探索与细胞膜(双层)相关的水在通过这种环境转移极性和带电分子中的作用。这一观点是在原子和分子水平上的！将使用已开发的新方法来描述水和渗透分子在截然不同的环境中移动时的不同分子性质。这项研究将解决膜中水和脂类之间的相互作用。具体地说，渗透分子局部环境中的水是否支持膜结构的变化，从而使分子稳定在“油性”脂类区域？更广泛地说，了解水在不同环境中的作用在许多科学和技术背景下都有意义(水介导的纳米颗粒的自组装、胶体悬浮液及其在环境中的作用等)，从而促进我们对这种普遍存在的溶剂及其在不同科学和技术重要化学环境中的行为的全球理解。这些新方法将继续应用在新的计算机硬件上，例如图形处理单元(GPU)，这些硬件现在正在成为日常计算的可行的商用高性能计算替代方案。广泛的影响受当前和未来不可避免的定量和定性科学学科之间合作的需求的推动，以加深我们对基本生物物理和生化过程的理解，将建立两个教育/推广目标。1)。一个由一名大学教授和两名资深教师(化学/物理和生物学)组成的多学科团队将向纽瓦克高中(NHS；该学校服务于大量少数族裔学生和在科学、技术和工程方面代表性较低的群体)的学生介绍一门计算化学入门课程，该课程将强调多学科方法的哲学，结合化学、生物、物理、数学和计算机科学领域的技能、工具和知识，以理解基本的生物物理现象。这将使学生接触到学术界和工业界广泛使用的实用计算机工具和技能。2)。为了支持特拉华大学化学和生物化学本科生的数学准备，并激发学生对生物物理、化学物理和计算科学等领域研究的更大兴趣，将开发一门计算化学入门课程，使用最先进的计算机和程序，侧重于化学数学，以解决化学性质的问题，并为学生学习严格的数学物理化学课程做准备。这种额外的准备和机会为化学学生磨练他们的基本数学技能将使物理化学对学生来说是一种不那么沉重的负担，更丰富(也许是有趣)的经历。项目目标有助于提高学生在职业生涯早期的定量推理技能，从而建立一个坚实的平台，从这个平台上进行与未来社会需求相关的众多研究途径。

Intellectual Merit Living cells have an inside and an outside, separated by a barrier called the cell membrane, primarily made of fundamental units called lipids. Molecules (such as salts, ions, polar molecules) that are happy (energetically stable) in water are not always happy in a membrane-like environment. Surprisingly, however, numerous water-loving molecules are found in the membrane or are known to cross the membrane environment quite easily. Cell penetrating peptides are observed to readily enter cells. Since water-loving molecules appear to reside within and transfer through the cell membrane, it is natural to think that water goes along for the ride. Water has an important role in these processes. Since it is impossible to see individual water molecules with laboratory experiments, computer programs will be used to perform what are known as molecular simulations. These computational methods, incorporating mathematical descriptions of the physics of how biological molecules interact with one another, follow the motions of individual molecules in time and space. This allows researchers to explore the role of water associated with cell membranes (bilayers) in the transfer of polar and charged molecules through this environment. The view is at the atomic and molecular level! Novel methods will be used that have been developed to describe the varying molecular properties of water and permeating molecules as they move through sharply different environments. The research will address the interaction between water and lipids in the membrane. Specifically, does the water present in the local environment of the permeating molecule support structural changes of the membrane that stabilize the molecule in the "oily" lipid region? More broadly, understanding the role of water in differing environments has implications in numerous scientific and technological contexts (water-mediated self-assembly of nanoparticles, colloidal suspensions and their role in the environment, etc.), thus furthering our global understanding of this ubiquitous solvent and its behavior across different scientifically and technologically important chemical environments. Application of these novel methods on new computer hardware such as Graphical Processing Units (GPU's) that are now becoming viable commodity high-performance computing alternatives for routine computing will be continued.Broader ImpactsMotivated by the inescapable current and future requirement for cooperation between the quantitative and qualitative scientific disciplines to further our understanding of fundamental biophysical and biochemical processes, two educational/outreach goals will be established. 1). A multi-disciplinary team consisting of a university professor and two veteran teachers (of chemistry/physics and biology) will introduce students at Newark High School (NHS; which serves a substantial population of minority students and groups underrepresented in science, technology, and engineering) to an introductory computational chemistry course that will emphasize a philosophy of multi-disciplinary approaches, combining the skill sets, tools, and knowledge of the fields of chemistry, biology, physics, math, and computer science, to understanding fundamental biophysical phenomena. This will expose students to practical computer tools and skills widely used in academia and industry. 2). To support the mathematics preparedness of undergraduate chemistry and biochemistry students at the University of Delaware, and to spark greater student interest in the pursuit of research in such fields as biophysics, chemical physics, and computational sciences, an introductory computational chemistry course will be developed, using state-of-the-art computers and programs, focusing on mathematics of chemistry to solve problems of a chemical nature and to prepare students for the mathematical rigor of Physical Chemistry courses. Such extra preparation and opportunities for chemistry students to sharpen their basic math skills will make Physical Chemistry a less burdensome, more enriching (and perhaps fun) experience for students. Project goals serve to increase students' quantitative reasoning skills at an early point in their careers, thus establishing a firm platform from which to pursue numerous avenues of research relevant to future societal needs.