MOLECULAR MODELNG OF COMPLEX BIOLOGICAL SYSTEMS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们正在申请TeraGrid访问，以便能够继续我们在生物系统中计算自由能量和自组装的工作。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。在解决第一个目标时，我们将重点放在纤维生物水解酶I(CBH1)上，这是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理对于实现生物质作为一种可行的可再生燃料至关重要。CBH1包含三个主要结构域--催化区、结合区和连接肽--它们协同作用降解纤维素和释放葡萄糖，葡萄糖是一种适合许多发酵过程的糖。虽然连接肽的序列是已知的，并且已经证明连接体在纤维素水解酶活性中起着重要作用，但连接体结构域所采用的空间构象尚不确定。我们将通过分子动力学模拟来探索这一点，在分子动力学模拟中，连接体在水环境中的运动和构象被监测。将进行平均作用力的势计算，以计算作为连接体长度的函数的连接体的自由能。TeraGrid的资源还将用于实现我们的第二个目标，即开发和测试原子化和粗粒度模型，以研究皮肤脂质的自组装。我们的目标是了解自组装所需的脂类，并确定形成的结构。实验研究表明，在角质层(皮肤的薄外层)，皮肤脂质以有序的凝胶或晶相组织，不同于大多数生物膜的典型液晶相，从而使它们能够起到有效的屏障作用。脂肪组织的形成与SC脂的独特组成有关，SC脂主要由神经酰胺、游离脂肪酸和胆固醇组成。虽然关于皮肤脂质的性质已知很多，但关于SC中脂质的分子组织的详细情况还没有阐明。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.