MODELING HYDROPHOBIC AND HYDROPHILIC INTERACTIONS

模拟疏水和亲水相互作用

• 批准号: 6385967
• 负责人: BRUCE J BERNE
• 金额: $ 21.91万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6385967
• 关键词: aspartic endopeptidases; chemical models; computer simulation; conformation; cyclosporines; enzyme substrate; intermolecular interaction; ionic bond; molecular dynamics; molecular polarity; peptides; peptidylprolyl isomerase; protein binding; quantum chemistry; thermodynamics; water solution

Computer modeling of complex liquids and biological systems is an important tool in biochemistry. With the increasing power of modern computers it is becoming possible to design new drugS and new biomimetic materials, and to gain understanding of molecular recognition, and the effects of mutationS on protein folding. One of the major aims of this proposal is the invention, extension and application of new methods to accelerate the stimulation and sampling of conformational states of biomolecular systems. We aim to further develop methods invented during the last grant period to treat systems with multiple time scales such as our reversible reference system propagator algorithms. Monte Carlo and molecular dynamics methods for sampling conformational states of biomolecules are often inherently quasi-ergodic. This means that starting in one stable conformation, not all other conformations can be reached on a practical time scale. We aim to devise methods for sampling conformation space in protein systems and other systems characterized by rough energy landscapes, and to apply these new methods to important problems involving the binding of peptides to enzymes and to conformational transitions of peptides. We aim to develop next generation polarizable force fields in order to deal a major impediment to rational drug design. Predictions of binding energies are dependent on the quality of the force field. Existing force fields do not account for known changes in atomic charges when a peptide undergoes a conformation change. Such effects require a chemically accurate polarizable force field that can correctly account for specific hydrogen bonding energies. During the preceding grant period we introduced a simple force field based on the principle of electronegativity equalization which has had remarkable success in predicting properties of water, NMA and analine dipeptide. We have shown that this model correctly accounts for three-body energies of many different kinds of trimers (eg clusters of analine dipeptide and water molecules). One of the major objectives of this proposal is to devise next generation polarizable force fields for peptides capable of giving chemical accuracy in the calculation of binding free energies when properly implemented in simulations using the new sampling methods discussed above. The proposed research will provide new methods and algorithms as well as a next generation force field for use in biological simulations. These methods will be used to study the binding of cyclosporin A to cyclophilin and the conformational transitions in HIV-1 protease.

复杂液体和生物系统的计算机建模是 生物化学的重要工具。 随着现代的越来越多的力量 计算机设计新药和新仿生剂的可能性 材料，并了解分子识别，并 突变对蛋白质折叠的影响。主要目的之一 提案是新方法的发明，扩展和应用 加速刺激和采样的构象状态 生物分子系统。 我们旨在进一步开发在 以多个时间尺度处理系统的最后一个赠款期 作为我们可逆的参考系统传播算法。 蒙特卡洛 和分子动力学方法用于取样的构象状态 生物分子通常是固有的准共产分子。 这意味着 从一个稳定的构象开始，并非所有其他构象都可以 达到实际时间范围。 我们的目标是设计方法 蛋白质系统和其他系统中的采样构象空间 以粗糙的能量景观为特征，并应用这些新方法 涉及肽与酶结合的重要问题 肽的构象转变。 我们旨在开发下一代可极化的力场，以便 造成理性药物设计的主要障碍。结合的预测 能量取决于力场的质量。 现存的 力场在A时未考虑已知的原子电荷变化 肽发生构象变化。 这样的效果需要一个 可以正确考虑的化学精确的极化力场 用于特定的氢键能。 在上一个赠款期间 时期我们根据原理引入了一个简单的力场 电负性均衡，在 预测水，NMA和分析二肽的特性。 我们有 表明该模型正确地说明了许多人的三体能量 不同种类的三聚体（例如，分析二肽和水的簇 分子）。 该提议的主要目标之一是设计 能够给予的肽的下一代可极化力场 计算结合自由能的化学精度 使用新的采样方法在模拟中正确实现 上面讨论了。 拟议的研究还将提供新的方法和算法 作为用于生物模拟的下一代力场。 这些方法将用于研究环孢菌素A与 HIV-1蛋白酶中的环磷脂和构象转变。