Computational Biophysics

我们的团队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VIRIAL展开。水溶液普遍存在于生物系统中。因此，细胞通常沐浴在离子、营养物质、多肽、蛋白质等的水溶液中。理论和模拟的目标是用分子间力来解释溶液的热力学(和其他)性质。在一篇经典但出了名的难的论文中，McMillan和Mayer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(在我们的情况下是水)，使溶质分子具有新的、有效的相互作用力，以及(B)以维里或溶质浓度系列扩大渗透压，系数(维里系数)以有效的溶质-溶质分子间相互作用的形式表示。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，并通过推导包括溶液热容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方法精确测量。通过比较实验得到的维里系数和模拟得到的维里系数，可以了解溶液中有效的溶质-溶质相互作用。我们将新理论应用于一个经典的测试案例--水中的苯，与渗透压和量热法实验相比，得到了很好的结果。我们建议将该理论应用于抗菌肽在溶液中的生物体系，为此我们刚刚进行了量热实验。小分子溶质的生物膜渗透性。细胞膜是一种选择性可渗透的屏障。大多数分子和离子需要特定的转运体才能穿过细胞膜，但水、氧气、其他小溶质和大多数药物只需简单的扩散就能穿过细胞膜。在现代理论中，分子的渗透率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)必须在分子水平上通过模拟获得。我们小组开发了新的有效和精确的方法，从同一模拟中同时获得W(Z)和D(Z)。用这些方法，我们计算了水、氧和酪胺(一种参与神经调节的痕量胺)的P，在有实验数据的地方，符合得很好。我们建议将膜渗透性理论扩展到考虑渗透时发生化学反应的分子。事实上，酪胺就是这种情况，它在中性形式和带电(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.