Computational Biophysics

我们小组在分子水平上模拟生物系统。该提案的两个主题是：* 稀溶液性质的维里展开。水溶液在生物系统中普遍存在。因此，一个细胞通常是沐浴在内部和外部的离子，营养物质，肽，蛋白质等的水溶液的理论和模拟的目标是解释热力学（和其他）解决方案的性质方面的分子间的力量。在一篇经典但难度极高的论文中，麦克米伦和迈耶提出了稀溶液热力学性质的理论。它包括两个阶段：（a）通过平均其分子运动来消除溶剂（在我们的情况下为水），使溶质分子具有新的有效相互作用力，以及（B），以维里或溶质浓度系列扩展渗透压，系数（维里系数）以有效溶质-溶质分子间相互作用表示。有效溶质相互作用可以通过分子模拟得到。 我们大大简化了推导过程，并通过推导包括溶解焓在内的许多其他性质的维里级数来扩展理论，这些性质可以用现代量热法精确测量。通过比较从实验中获得的维里系数与通过模拟获得的维里系数，人们可以了解溶液中有效的溶质-溶质相互作用。我们已经将新的理论应用到一个经典的测试案例，苯在水中，与渗透压和量热实验相比，具有良好的效果。我们建议将这一理论应用于抗菌肽在溶液中的生物体系，我们刚刚做了量热实验。** 小溶质的生物膜渗透性。细胞膜是一种选择性渗透屏障。大多数分子和离子需要特定的转运蛋白才能穿过膜，但水、氧气、其他小溶质和大多数药物通过简单的扩散穿过膜。在现代理论中，预测分子的渗透性P取决于在跨膜的点z处与膜的有效相互作用势w（z）以及局部扩散系数D（z）。量w（z）和D（z）必须通过分子水平的模拟获得。我们的小组已经开发出新的有效和准确的方法，从同一个模拟同时获得w（z）和D（z）。用这些方法，我们已经计算了水，氧和酪胺（一种微量胺参与神经调节）的P，并在实验数据存在的情况下，协议是好的。我们建议扩展膜渗透性理论，以解释渗透时发生化学反应的分子。事实上，酪胺就是这种情况，它在中性和带电（质子化）形式之间相互转化，到目前为止，我们忽略了这种相互转化。

Our group simulates biological systems at the molecular level. The two themes of the proposal are:****VIRIAL EXPANSIONS FOR PROPERTIES OF DILUTE SOLUTIONS. Aqueous solutions are ubiquitous in biological systems. Thus a cell is usually bathed on both inside and outside by aqueous solutions of ions, nutrients, peptides, proteins, etc. The goal of theory and simulation is to explain the thermodynamic (and other) solution properties in terms of the intermolecular forces. In a classic but notoriously difficult paper, McMillan and Mayer presented a theory for the thermodynamic properties of dilute solutions. It involves two stages: (a) eliminating the solvent (water in our case) by averaging over its molecular motions, leaving the solute molecules with new, effective, interaction forces, and (b), expanding the osmotic pressure in a virial or solute concentration series, with coefficients (the virial coefficients) expressed in terms of the effective solute-solute intermolecular interactions. The effective solute interactions can be obtained by molecular simulation. We have greatly simplified the derivations, and extended the theory by deriving virial series for a number of other properties including the solution enthalpy, which can be measured accurately with modern calorimetry methods. By comparing virial coefficients obtained from experiment with those obtained by simulation, one learns about the effective solute-solute interactions in solution. We have applied the new theory to a classic test case, benzene in water, with good results when compared with osmotic pressure and calorimetry experiments. We propose to apply the theory to the biological system of antimicrobial peptides in solution, for which we have just done calorimetry experiments. **BIOMEMBRANE PERMEABILITY OF SMALL SOLUTES. The cell membrane is a selectively permeable barrier. Most molecules and ions require specific transporters to cross the membrane, but water, oxygen, other small solutes and most drugs cross it by simple diffusion. In the modern theory the permeabilty P of a molecule is predicted to depend on the effective interaction potential with the membrane w(z) at points z across the membrane, and on the local diffusion coefficient D(z). The quantities w(z) and D(z) must be obtained by simulation at the molecular level. Our group has developed new efficient and accurate methods to obtain w(z) and D(z) simultaneously from the same simulation. With these methods we have calculated P for water, oxygen and tyramine (a trace amine involved in neuroregulation), and where experimental data exist, agreement is good. We are proposing to extend the theory of membrane permeability to account for molecules which chemically react while permeating. This is in fact the case with tyramine, which interconverts between a neutral and a charged (protonated) form, and up to the present time we have neglected the interconversion.**