Halogen bonds in biomolecular design

卤键（X键）的研究几乎在化学和材料科学的所有领域都在增长。在生物学和生物化学中，X-键具有极大的潜力，可以促进针对酶靶点的新型卤代抑制剂的合理设计。该项目采用全面的策略来研究结构如何影响DNA和蛋白质中生物分子X键的能量。该项目正在开发一种独特的计算工具，可供生物学家，生物化学家和化学生物学家使用，以合理设计针对重要酶的新抑制剂。该工具还将用于帮助设计新的生物基材料。该项目对社会的影响是通过教育推广项目让K-12级的学生参与体验式学习，提高未来劳动力的科学素养。这个外展项目向高中生介绍了结构生物学中的两个重要概念：1）三维蛋白质结构的基本原理和2）这些结构是如何通过实验确定的。最后，向不同群体的学生提供研究培训，从高中到博士后，包括性别、种族和经济背景。所提出的研究的驱动假设是，生物卤素键（ffBXB）的力场，一旦纳入分子力学/动力学程序，可以准确和有效地应用于设计新的卤化分子的生物工程应用。该项目在标准分子模拟程序中实现和测试ffBXB。该程序的测试，其准确建模的结构和能量的X-键，涉及正式带负电荷的氧受体在以前的实验模型DNA结的能力。新的程序是独立的交叉验证，其准确建模的结构和能量的X-键，涉及正式中性氧受体在模型DNA连接和T4溶菌酶的能力。通过这些分子系统的X射线晶体学原子水平结构测定并通过差示扫描量热法（DSC）在溶液中测量其相互作用能进行验证研究。自由能微扰方法被用来研究工程X-键的构象和溶剂动力学的生物系统的影响。通过应用ffBXB设计新的蛋白质-蛋白质界面来测试主要假设。已经设计了卷曲螺旋多肽模型系统，其中引入卤代氨基酸以充当适合工程化受体“孔”的X键供体“旋钮”。由此产生的“X-拉链”作为一个概念的证明，X-键可以用来促进蛋白质的特定组装在一个合理的方式。

The study of halogen bonds (X-bonds) is growing in nearly all fields of chemistry and material science. In biology and biochemistry, X-bonds have great potential to facilitate the rational design of new halogenated inhibitors against enzyme targets. This project applies a comprehensive strategy to study how structure affects the energy of biomolecular X-bonds in DNA and proteins. This project is developing a unique computational tool that can be used by biologists, biochemists and chemical biologists to rationally design new inhibitors against important enzymes. The tool would also be used to aid design of new biologically-based materials. The impact of this project on society is to improve the scientific literacy of the future workforce by engaging students at the K-12 level with experiential learning through an educational outreach project. This outreach project is introducing high school students to two important concepts in structural biology: 1) the fundamentals of 3-dimensional protein structures and 2) how those structures are experimentally determined. Finally, research training is provided to diverse groups of students, ranging from high school to postdoctoral levels, inclusive of gender, ethnicity and economic background. The driving hypothesis of the proposed studies is that a force field for biological halogen bonds (ffBXB), once incorporated into a molecular mechanics/dynamics program, can be accurately and efficiently applied to design novel halogenated molecules for bioengineering applications. The project implements and tests the ffBXB in a standard molecular simulation program. The program is tested for its ability to accurately model the structures and energies of X-bonds that involve formally negatively charged oxygen acceptors in a previously-characterized experimental model DNA junction. The new program is independently cross-validated for its ability to accurately model the structures and energies of X-bonds that involve formally neutral oxygen acceptors in the model DNA junction and in T4 lysozyme. The validation studies are performed by X-ray crystallographic atomic level structure determination of these molecular systems and measuring their energies of interaction by differential scanning calorimetry (DSC) in solution. Free energy perturbation methods are used to study the effects of engineered X-bonds on the conformational and solvent dynamics of a biological system. The primary hypothesis is tested by applying the ffBXB to design new protein-protein interfaces. A coiled-coil polypeptide model system has been designed in which halogenated amino acids are introduced to serve as X-bond donating "knobs" that fit into engineered acceptor "holes". The resulting "X-Zipper" serves as a proof of concept that X-bonds can be used to facilitate specific assembly of proteins in a rational manner.