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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >A method for optimizing potential-energy functions by a hierarchical design of the potential-energy landscape: Application to the UNRES force field
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A method for optimizing potential-energy functions by a hierarchical design of the potential-energy landscape: Application to the UNRES force field

机译：通过势能态势的分层设计优化势能函数的方法：在UNRES力场中的应用

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A method for optimizing potential-energy functions of proteins is proposed. The method assumes a hierarchical structure of the energy landscape, which means that the energy decreases as the number of native-like elements in a structure increases, being lowest for structures from the native family and highest for structures with no native-like element. A level of the hierarchy is defined as a family of structures with the same number of native-like elements (or degree of native likeness). Optimization of a potential-energy function is aimed at achieving such a hierarchical structure of the energy landscape by forcing appropriate free-energy gaps between hierarchy levels to place their energies in ascending order. This procedure is different from methods developed thus far, in which the energy gap and/or the Z score between the native structure and all non-native structures are maximized, regardless of the degree of native likeness of the non-native structures. The advantage of this approach lies in reducing the number of structures with decreasing energy, which should ensure the searchability of the potential. The method was tested on two proteins, PDB ID codes 1FSD and 1IGD, with an off-lattice united-residue force field. For 1FSD, the search of the conformational space with the use of the conformational space annealing method and the newly optimized potential-energy function found the native structure very quickly, as opposed to the potential-energy functions obtained by former optimization methods. After even incomplete optimization, the force field obtained by using 1IGD located the native-like structures of two peptides, 1FSD and betanova (a designed three-stranded β-sheet peptide), as the lowest-energy conformations, whereas for the 46-residue N-terminal fragment of staphylococcal protein A, the native-like conformation was the second-lowest-energy conformation and had an energy 2 kcal/mol above that of the lowest-energy structure.
机译：提出了一种优化蛋白质势能功能的方法。该方法假定能量格局的层次结构，这意味着能量随着结构中类似自然元素的数量增加而减少，对于来自自然族的结构最低，而对于没有自然元素的结构则最高。层次结构的级别定义为具有相同数量的类似原生元素（或类似程度）的结构族。势能函数的优化旨在通过在层次结构级别之间强制适当的自由能缺口，使它们的能量按升序排列，从而实现能源格局的这种层次结构。此过程与迄今为止开发的方法不同，在该方法中，本机结构与所有非本机结构之间的能隙和/或Z分数均最大化，而与非本机结构的本机相似程度无关。该方法的优点在于，通过减少能量来减少结构的数量，这应确保电位的可搜索性。该方法在两种蛋白质（PDB ID码1FSD和1IGD）上进行了测试，并具有非晶格联合残余力场。对于1FSD，使用构象空间退火方法和新优化的势能函数对构象空间进行搜索，与通过以前的优化方法获得的势能函数非常快地找到了天然结构。经过甚至不完全优化后，使用1IGD获得的力场将两种能量的天然结构（1FSD和betanova（一种设计的三链β-折叠肽））定位为最低能量构象，而对于46个残基金黄色葡萄球菌蛋白A的N-末端片段是天然的构象，是能量第二低的构象，其能量比最低能量的结构高2 kcal / mol。

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