Realistic protein folding with hydrophobic potentials

描述(由申请人提供) 这项研究是美国国立卫生研究院#RO1-GM52126号补助金的延伸，将主要在巴西巴西利亚大学与安东尼奥·F·佩雷拉·德阿劳霍合作进行。作为一个广泛的、长期的目标，它打算在寻找适合于现实蛋白质模型的从头计算折叠模拟的势能函数方面做出贡献，这将使根据蛋白质的氨基酸序列预测蛋白质结构成为可能。更具体地说，外国合作者小组在极简主义晶格模型的背景下研究的未指定的疏水势，将与一个现实的非晶格模型相结合，所有蛋白质重原子都明确地表示出来，这是开发出来的，并已在主要研究人员的小组中使用。与通常使用的更具体的能量函数相比，疏水势的主要优势是它依赖于实际数量较少的参数，即每个单体或原子的疏水性，取决于模型，因此，最终有更大的机会被编码在氨基酸序列中。然而，这种少量的参数意味着，即使在晶格模型中，也很难为给定的固有结构找到适当的参数组合。由于非晶格模型的巨大灵活性预计会显著加剧这一问题，因此将不得不应用与序列无关但物理动机的结构限制，主要是以主干氢键的形式。该项目的主要近期目标是调查由非特定疏水相互作用主导的势在多大程度上可以与物理驱动的结构限制相结合来折叠现实的、非晶格的蛋白质模型。

DESCRIPTION (provided by applicant) This research, an extension of NIH grant #RO1-GM52126, will be performed primarily in Brazil at the University of Brasilia in collaboration with Antonio F. Pereira de Araujo. As a broad, long-term objective, it intends to contribute in the search for a potential energy function appropriate for ab initio folding simulations of realistric protein models, which would possibilitate the prediction of protein structures from their amino acid sequences. More specifically, an unspecified hydrophobic potential, which has been studied by the foreign collaborator's group in the context of minimalist lattice models, will be combined with a realistic, off-lattice model, with all protein heavy atoms represented explicitly, which was developed and has been used in the principal investigator's group. The main advantage of the hydrophobic potential over more specific energy functions normally used is that it depends on a realtively small number of parameters, that is, the hydrophobicity of each monomer or atom, depending on the model, and, therefore, has a greater chance of being eventually encoded in the sequence of amino acids. This small number of parameters, however, implies that it is much harder, even in lattice models, to find the appropriate combination of parameters for a given native structure. Since the large flexibility of the off-lattice model is expected to aggravate this problem dramatically, sequence independent but physically motivated structural restrictions, mainly in the form of backbone hydrogen bonds, will have to be appied. The main immediate goal of the project is then to investigate to what extent a potential dominated by unspecific hydrophobic interactions, which can be obtained by the approach previously developed in the context of lattice models, can be combined with physically motivated structural restrictions to fold realistic, off-lattice, protein models.