INTERACTIONS OF ANESTHETICS WITH WATER-LIPID INTERFACES

本项目的目的是确定麻醉剂的化合物 兴趣与脂质膜相互作用， 这些化合物在水膜界面上的结构 类似的化合物，每一种都从强效麻醉剂到非 麻醉剂，将被确定为测试假设，麻醉剂 只有当界面处的麻醉剂浓度 就足够了这一假设是由埃格最近的发现激发的 亲脂性本身不足以预测 吸入麻醉剂还需要最低程度的亲水性 来产生麻醉。 在所提出的计算的第一阶段，势能 在分子动力学计算所需的功能，将被设计和 通过比较所选化合物在 水和己烷与测量的溶解度。然后， 这些化合物穿过日益复杂的界面（水-己烷， 水-糖脂、水-磷脂）。的结合 麻醉剂的接口将被分析方面的扰动 在膜的结构和由这些产生的界面水中 化合物. 麻醉药相互作用的分子基础 vs.具有水-膜界面的非麻醉化合物将 推进我们对麻醉作用部位和机制的认识。 改善麻醉剂和理化性质之间的相关性 麻醉剂的化合物，应该从拟议的计算结果， 将有助于未来设计更好的麻醉剂。

The objective of this project are to define how compounds of anesthetic interest interact with lipid membranes and to correlate the concentration of these compounds at the water-membranes interface with structurally similar compounds, each ranging from potent anesthetics to non anesthetics, will be determined to test the hypothesis that an anesthetic effect occurs only when the concentration of anesthetic at the interface is sufficient. This hypothesis is motivated by recent findings by Eger that lipophilicity alone is not sufficient to predict the potency of inhaled anesthetics. A minimum level of hydrophilicity is also required to produce anesthesia. In the first stage of the proposed calculations, the potential energy functions needed in molecular dynamics calculations, will be designed and tested by comparing calculated solubilities of the selected compounds in water and hexane with the measured solubilities. Then, the transfer of these compounds across interfaces of increasing complexity (water-hexane, water-glycolipid, water-phospholipid) will be simulated. The binding of anesthetics to the interface will be analyzed in terms of perturbations in the structure of membranes and interfacial water created by these compounds. An understanding of the molecular basis for interactions of anesthetic vs. non anesthetic compounds with the water-membrane interface will advance our knowledge of the site and mechanism of anesthetic action. Improved correlation between anesthetic and physical-chemical properties of anesthetic compounds that should result from the proposed calculations will be helpful in future effects to design better anesthetics.