A Simplified Potential for Protein Folding Simulations

描述(由申请人提供)： 生物体的功能在很大程度上取决于这样一个事实，即它的每个组成蛋白在生理条件下采用一个独特的结构(所谓的天然结构)；这种结构由氨基酸序列和环境决定。根据安芬森的热力学假说，蛋白质的天然构象是其自由能超曲面上的全局能量极小值。因此，如果可以得到准确的势能函数，则可以在该超曲面中寻找本征结构作为全局最小值。蛋白质的自由能超曲面的形状非常复杂，很难描述。出于效率的原因，必须使用多肽链的简化模型，其中每个氨基酸残基由一个或几个相互作用位点表示，而不是全原子拆分模型。虽然我们以前的重点是全局优化方法，但现在我们的重点是基于物理的联合剩余UNRES势能函数。其主要目标是仅基于势能的全局优化来预测所有主要结构类别(α、β、αβ和α/β)的蛋白质的结构，其链长最长可达200个氨基酸残基，均方根偏差在4-6埃内。这将通过改进单个能量分量的函数形式和参数来实现，并通过优化总能量函数以反映部分展开结构的能量等级来确保势的折叠特性。了解物理相互作用在蛋白质天然结构形成中的作用将使我们不仅能够仅基于氨基酸序列的知识来预测蛋白质的最终结构，而且还可以用于研究蛋白质的折叠或错误折叠过程。预测蛋白质的三维结构或预测其折叠路径的能力可以极大地有助于合理设计抗癌、阿尔茨海默病或普里恩病的药物。

DESCRIPTION (provided by applicant): The functioning of living organisms is largely dependent on the fact that each of its constituent proteins adopts a unique structure (the so-called native structure) under physiological conditions; this structure is determined by amino-acid sequence and its environment. According to Anfinsen's thermodynamic hypothesis, the native conformation of a protein is a global-energy minimum on its free-energy hypersurface. The native structure can therefore be sought as the global minimum in this hypersurface, if an accurate potential energy function is available. The shape of the free-energy hypersurface of proteins is very complex and difficult to describe. For efficiency reasons, simplified models of polypeptide chains, in which each amino-acid residue is represented by one or a few interaction sites rather than all-atom resolution models, must be used. While our previous focus was on global optimization methods, it is now focused on our physics-based united-residue UNRES potential-energy function. The main goal is to predict the structure of proteins of all major structural classes (alpha, beta, alpha+beta and alpha/beta) with chain lengths of up to 200 amino-acid residues within 4-6 Angstrom root mean square deviation based solely on global optimization of the potential energy. This will be accomplished by improving the functional forms and parameters of individual energy components and assuring the folding property of the potential by optimizing the total energy function to reflect the energetic hierarchy of partially unfolded structures. Understanding of the role of physical interactions in the formation of the native structur e of the protein will enable us not only to predict the final structure of the protein based only on knowledge of the amino-acid sequence but can be used to study protein folding or misfolding processes. The ability to predict three-dimensional structures of proteins or to predict their folding pathways can greatly contribute to rational drug design against cancer, Alzheimer or prion deseases.