MOLECULAR MODELNG OF COMPLEX BIOLOGICAL SYSTEMS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们正在请求TeraGrid访问，以便继续我们在生物系统中计算自由能和自组装的工作。特别是，我们有两个目标：第一，了解纤维素酶的作用机制，第二，研究皮肤脂质的自组装。在解决第一个目标，我们专注于纤维二糖水解酶I（CBH 1），已知的最活跃的纤维素酶之一。因此，了解其对纤维素的作用机制对于实现生物质作为可行的可再生燃料至关重要。CBH 1包含三个主要结构域-催化结构域、结合结构域和连接肽-它们协同作用以水解纤维素并释放葡萄糖，葡萄糖是一种适合于许多发酵过程的糖。虽然接头肽的序列是已知的，并且已经表明接头在纤维素水解期间的酶活性中起重要作用，但接头结构域所采用的空间构象尚未确定。我们将通过分子动力学模拟来探测这一点，其中监测连接体在水性环境中的运动和构象。将进行平均力计算，以计算作为连接体长度函数的连接体自由能。TeraGrid资源还将用于解决我们的第二个目标，即开发和测试原子和粗粒度模型，以研究皮肤脂质的自组装。我们的目标是了解什么脂质需要自组装，并确定形成的结构。实验研究表明，在角质层（皮肤的薄外层）中，皮肤脂质以有序的凝胶或结晶相组织，与大多数生物膜的典型液晶相不同，从而使它们能够起到有效屏障的作用。脂质组织可归因于SC脂质的独特组成，其主要由神经酰胺、游离脂肪酸和胆固醇组成。虽然对皮肤脂质的性质了解很多，但SC中脂质分子组织的详细情况尚未阐明。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We are requesting TeraGrid access to enable the continuation of our work on the calculation of free energies and self-assembly in biological systems. In particular, we have two goals: first, to understand the mechanism of action of cellulase enzymes, and, second, to study the self-assembly of skin lipids. In addressing the first goal, we focus on cellobiohydrolase I (CBH1), one of the most active cellulose enzymes known. Therefore, understanding its mechanism of action on cellulose is central to realizing biomass as a viable renewable fuel. CBH1 contains three principal domains - the catalytic domain, binding domain and linker peptide - that function cooperatively to hydrolyze cellulose and liberate glucose, a sugar suitable for many fermentative processes. Although the sequence of the linker peptide is known and it has been shown that the linker plays an important role in enzymatic activity during cellulose hydrolysis, the spatial conformation adopted by the linker domain is yet to be determined. We will probe this through molecular dynamics simulations in which the motion and conformation of the linker in an aqueous environment are monitored. Potential of mean force calculations will be performed to compute the free energy of the linker as a function of linker length. TeraGrid resources will additionally be to address our second goal, the development and testing of atomistic and coarse-grained models in order to study the self-assembly of skin lipids. We aim to understand what lipids required for self-assembly and to determine the structures formed. Experimental studies have shown that in the stratum corneum (the thin, outer layer of the skin), the skin lipids are organized in ordered gel or crystalline phases, unlike the typical liquid crystalline phases of most biological membranes, thus enabling them to function as an effective barrier. The lipid organization can be ascribed to the unique composition of the SC lipids, which is composed of mostly ceramides, free fatty acids and cholesterol. While much is known about the nature of the skin lipids, a detailed picture of the molecular organization of lipids in the SC has not been elucidated.