Discrimination of the native from misfolded protein models with an energy function including implicit solvation
Discrimination of the native from misfolded protein models with an energy function including implicit solvation
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DOI：
10.1006/jmbi.1999.2685
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发表时间：
1999-05-07
影响因子：
5.6
通讯作者：
Karplus, M
中科院分区：
文献类型：
--
作者：
Lazaridis, T;Karplus, M
理论蛋白质结构预测的一个基本要求是一个能区分天然和非天然蛋白质构象的能量函数。迄今为止，用于此目的的大多数能量函数都是从蛋白质结构数据库的统计分析中提取的，没有明确提及负责蛋白质稳定性的物理相互作用。统计函数的使用得到了广泛的支持，人们普遍认为，统计函数比基于物理的能量函数在这种区分方面更优越。将CHARMM真空势与溶剂化自由能的高斯模型相结合的有效能量函数用于区分蛋白质的天然结构和错误折叠构象的能力。并与真空CHARMM势的计算结果进行了比较。该测试是在其他人制备的几组错误折叠结构上进行的，包括六种蛋白质的约650组良好诱饵，以及糜凝胰蛋白酶抑制剂2的错误折叠结构。当考虑能量最小化构象时，真空CHARMM势在大多数情况下是成功的，但当应用于分子动力学松弛的结构时就失败了。在有效能量函数下，无论在能量最小化结构还是分子动力学松弛结构中，固有态总是比严重错误折叠的构象更稳定。目前的结果表明，分子力学（基于物理的）能量函数，加上一个简单的溶剂化自由能模型，应该用于反折叠问题的测试，并支持它们在溶液中蛋白质有效能表面的研究中使用。此外，研究表明，相信统计函数在这些目的上的优越性可能是没有根据的。(C) 1999学术出版社。
An essential requirement for theoretical protein structure prediction is an energy function that can discriminate the native from non-native protein conformations. To date most of the energy functions used for this purpose have been extracted from a statistical analysis of the protein structure database, without explicit reference to the physical interactions responsible for protein stability. The use of the statistical functions has been supported by the widespread belief that they are superior for such discrimination to physics-based energy functions. An effective energy function which combined the CHARMM vacuum potential with a Gaussian model for the solvation free energy is tested for its ability to discriminate the native structure of a protein from misfolded conformations; the results are compared with those obtained with the vacuum CHARMM potential. The test is performed on several sets of misfolded structures prepared by others, including sets of about 650 good decoys for six proteins, as well as on misfolded structures of chymotrypsin inhibitor 2. The vacuum CHARMM potential is successful in most cases when energy minimized conformations are considered, but fails when applied to structures relaxed by molecular dynamics. With the effective energy function the native state is always more stable than grossly misfolded conformations both in energy minimized and molecular dynamics-relaxed structures. The present results suggest that molecular mechanics (physics-based) energy functions, complemented by a simple model for the solvation free energy, should be tested for use in the inverse folding problem, and supports their use in studies of the effective energy surface of proteins in solution. Moreover, the study suggests that the belief in the superiority of statistical functions for these purposes may be ill founded. (C) 1999 Academic Press.