Modeling Hydrophobic and Hydrophilic Interactions

描述(申请人提供)：复杂液体和生物系统的计算机模拟是生物化学中的一个重要工具。随着现代计算机能力的增强，设计新的药物和新的仿生材料成为可能，并获得对分子识别和突变对蛋白质折叠的影响的理解。这一建议的主要目的之一是发明、推广和应用新的方法来加速生物分子体系构象状态的模拟和采样。蒙特卡罗和分子动力学方法采样生物分子的构象状态通常是准遍历的。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时间尺度上达到。我们的目标是设计在蛋白质系统和其他以粗糙能量为特征的系统中采样构象空间的方法，并将这些新方法应用于涉及多肽与酶的结合和多肽的构象转变的重要问题。我们的目标是开发下一代可极化力场，以解决合理药物设计的主要障碍。结合能的预测取决于力场的质量。当一个肽发生构象变化时，现有的力场不能解释原子电荷的已知变化。这种效应需要一个化学上准确的可极化力场，能够正确地解释特定的氢键能量。在之前的授权期内，我们在分子的指定位置上分配了浮动电荷和浮动偶极子。该模型在预测水、离子溶液、氨基酸和二肽的性质方面取得了显著的成功。我们已经证明，这些方法将被用于研究蛋白质G的b-发夹C-末端的构象动力学；(B)同源和杂寡肽的螺旋-螺旋转变；(C)环孢素A与亲环素的结合；以及(D)HIV-1蛋白的构象转变。该研究将为生物模拟提供新的方法和算法以及下一代力场。这些方法将被用来研究环孢素A与环孢素A的结合以及HIV-1的构象转变

DESCRIPTION (provided by applicant): 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 simulation and sampling of conformational states of biomolecular systems. 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 based an assigning fluctuating charges and fluctuating dipoles on designated sites on the molecule. This modet has had remarkable success in predicting properties of water, ion solution, amino acids and dipeptides. We have shown that these methods will be used to study conformational dynamics in the (a) of the b-hairpin C-terminus of protein G; (b) the helix-coil transition of homo and hetero oligopeptides; (C) the binding of cyclosporin A to cyclophilin; and (d) conformational transitions in HIV-1 protease.The proposed research will provide new methods and algorithms as well as next generation force field for use in biological simulations. These methods wilt be used to study the binding of cyclosporin A to cvctoohilin and the conformational transitions in HIV-1