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，即它的每一个组成蛋白质在生理条件下都采用一种独特的结构（所谓的天然结构）;这种结构是由氨基酸序列及其环境决定的。根据Anfinsen的热力学假设，蛋白质的天然构象是其自由能超曲面上的全局能量最小值。因此，如果有一个精确的势能函数，自然结构可以作为这个超曲面中的全局最小值来寻找。蛋白质自由能超曲面的形状非常复杂，难以描述。出于效率的原因，必须使用简化的多肽链模型，其中每个氨基酸残基由一个或几个相互作用位点表示，而不是全原子分辨率模型。虽然我们以前的重点是全局优化方法，它现在集中在我们的基于物理的联合剩余UNRES势能函数。主要目标是预测所有主要结构类别（α、β、α + β和α/β）的蛋白质的结构，其中链长高达200个氨基酸残基，仅基于势能的全局优化，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来确保势能的折叠性质，以反映部分未折叠结构的能量层次。了解物理相互作用在蛋白质天然结构形成中的作用，不仅使我们能够仅根据氨基酸序列的知识预测蛋白质的最终结构，而且可以用于研究蛋白质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途径的能力可以极大地有助于针对癌症、阿尔茨海默病或朊病毒疾病的合理药物设计。

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.