MODELING HYDROPHOBIC AND HYDROPHILIC INTERACTIONS

复杂液体和生物系统的计算机建模是一种 生物化学中的重要工具。随着现代社会的力量不断增强 计算机正在成为设计新药和新仿生药物的可能 材料，并了解分子识别，以及 突变对蛋白质折叠的影响。这次会议的主要目的之一是 建议是新方法的发明、推广和应用 加快对构象状态的模拟和采样 生物分子系统。我们的目标是进一步开发在 处理具有多个时间尺度的系统的最后一个授权期，如 作为我们的可逆参考系统传播子算法。蒙特卡洛 和分子动力学方法对构象状态进行采样 生物分子往往天生就是准遍历的。这意味着 从一个稳定的构象开始，并不是所有其他构象都可以 在实际的时间尺度上达成了。我们的目标是设计出方法来 蛋白质体系和其他体系中的采样构象空间 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，以及 到多肽的构象转变。 我们的目标是开发下一代可极化力场，以便 对合理的药物设计造成了重大障碍。关于绑定的预测 能量取决于力场的质量。现有 力场不能解释原子电荷的已知变化 多肽发生构象变化。这样的效果需要一个 化学上精确的极化力场，可以正确地计算 以获得特定的氢键能量。在上一次拨款期间 期间，我们引入了一个简单的力场，其原理是 电负性均衡在以下方面取得了显著成功 预测水、N-甲基-N-甲基-天冬氨酸和苯丙氨酸二肽的性质。我们有 表明这个模型正确地解释了许多 不同种类的三聚体(如一连串的二肽和水) 分子)。这项提案的主要目标之一是设计出 下一代能够给出的多肽的极化力场 计算结合自由能时的化学精确度 在使用新的抽样方法的模拟中得到适当实施 如上所述。 提出的研究也将提供新的方法和算法。 作为用于生物模拟的下一代力场。 这些方法将被用来研究环孢菌素A与 亲环素与HIV-1蛋白酶的构象转变。

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.