van der Spoel D, Vogel H J, Berendsen H J
Department of Biophysical Chemistry, University of Groningen, The Netherlands.
Proteins. 1996 Apr;24(4):450-66. doi: 10.1002/(SICI)1097-0134(199604)24:4<450::AID-PROT5>3.0.CO;2-I.
Molecular dynamics (MD) simulations of N-terminal peptides from lactate dehydrogenase (LDH) with increasing length and individual secondary structure elements were used to study their stability in relation to folding. Ten simulations of 1-2 ns of different peptides in water starting from the coordinates of the crystal structure were performed. The stability of the peptides was compared qualitatively by analyzing the root mean square deviation (RMSD) from the crystal structure, radius of gyration, secondary and tertiary structure, and solvent accessible surface area. In agreement with earlier MD studies, relatively short (< 15 amino acids) peptides containing individual secondary structure elements were generally found to be unstable; the hydrophobic alpha 1-helix of the nucleotide binding fold displayed a significantly higher stability, however. Our simulations further showed that the first beta alpha beta supersecondary unit of the characteristic dinucleotide binding fold (Rossmann fold) of LDH is somewhat more stable than other units of similar length and that the alpha 2-helix, which unfolds by itself, is stabilized by binding to this unit. This finding suggests that the first beta alpha beta unit could function as an N-terminal folding nucleus, upon which the remainder of the polypeptide chain can be assembled. Indeed, simulations with longer units (beta-alpha-beta-alpha and beta-alpha-beta-alpha beta-beta) showed that all structural elements of these units are rather stable. The outcome of our studies is in line with suggestions that folding of the N-terminal portion of LDH in vivo can be a cotranslational process that takes place during the ribosomal peptide synthesis.
利用乳酸脱氢酶（LDH）不同长度的N端肽段以及单个二级结构元件进行分子动力学（MD）模拟，以研究它们与折叠相关的稳定性。从晶体结构坐标开始，对不同肽段在水中进行了10次1 - 2纳秒的模拟。通过分析与晶体结构的均方根偏差（RMSD）、回转半径、二级和三级结构以及溶剂可及表面积，对肽段的稳定性进行了定性比较。与早期的MD研究一致，通常发现含有单个二级结构元件的相对较短（<15个氨基酸）的肽段不稳定；然而，核苷酸结合结构域的疏水α1螺旋显示出明显更高的稳定性。我们的模拟进一步表明，LDH特征性二核苷酸结合结构域（Rossmann结构域）的第一个β-α-β超二级单元比其他类似长度的单元稍微更稳定，并且自行展开的α2螺旋通过与该单元结合而稳定。这一发现表明，第一个β-α-β单元可以作为N端折叠核，多肽链的其余部分可以在此基础上组装。实际上，对更长单元（β-α-β-α和β-α-β-α-β-β）的模拟表明，这些单元的所有结构元件都相当稳定。我们的研究结果与以下观点一致，即体内LDH N端部分的折叠可能是核糖体肽合成过程中发生的共翻译过程。
