Computational Biophysics

我们的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无处不在。因此，细胞的内外通常都沐浴在离子、营养物质、多肽、蛋白质等的水溶液中。理论和模拟的目的是根据分子间作用力来解释热力学（和其他）溶液性质。在一篇经典但又出了名的难的论文中，麦克米伦和迈耶提出了一个关于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（在我们的例子中是水），使溶质分子具有新的、有效的相互作用力，以及(b)扩大渗透压力在一个维里或溶质浓度系列中，系数（维里系数）用有效的溶质-溶质分子间相互作用来表示。通过分子模拟可以得到有效的溶质相互作用。我们极大地简化了推导，并扩展了理论，推导了许多其他性质的维里级数，包括可以用现代量热法精确测量的溶液焓。通过对比实验和模拟得到的维里系数，可以了解溶液中溶质-溶质的有效相互作用。我们将新理论应用于苯在水中的经典测试案例，并与渗透压和量热实验进行了比较，结果良好。我们建议将这一理论应用于溶液中抗菌肽的生物系统，我们已经为此做了量热实验。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体才能穿过膜，但水、氧、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，分子的透性P被预测取决于在穿过膜的z点处与膜的有效相互作用势w(z)和局部扩散系数D(z)。w(z)和D(z)必须在分子水平上通过模拟得到。本课组开发了一种新的高效、准确的方法，可以在同一次模拟中同时获得w(z)和D(z)。利用这些方法，我们计算了水、氧和酪胺（一种参与神经调节的微量胺）的P，并且在实验数据存在的地方，一致性很好。我们建议扩展膜渗透性理论，以解释在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，我们一直忽略了相互转化。

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.