Abkevich V I, Gutin A M, Shakhnovich E I
Department of Chemistry, Harvard University, Cambridge, MA 02138, USA.
Fold Des. 1996;1(3):221-30. doi: 10.1016/S1359-0278(96)00033-8.
A number of approaches to design stable and fast-folding sequences for model polypeptide chains have been based on the premise that optimization of the relative energy of the native conformation (or Z-score) is sufficient to yield stable and fast-folding sequences. Although this approach has been successful, for longer chains it often yielded sequences that failed to fold cooperatively, instead having multidomain folding behavior.
We show that one of the factors determining single-domain or multidomain folding behavior is the dispersion of energies of native contacts. So, we study folding of sequences optimized to have the same native conformation as a global energy minimum but having different dispersion of native contact energies. Our results suggest that under conditions at which native conformation is stable, the best-folding proteins are those that have smaller heterogeneity of native contact energies. For them, the folding transition is all-or-none. On the other hand, proteins with greater heterogeneity of native contact energies have more gradual multidomain folding transition and fold into stable native conformation much slower than those proteins with small dispersion of native contact energies.
许多为模型多肽链设计稳定且快速折叠序列的方法都基于这样一个前提，即对天然构象的相对能量（或Z分数）进行优化足以产生稳定且快速折叠的序列。尽管这种方法已经取得了成功，但对于较长的链，它常常产生无法协同折叠的序列，而是具有多结构域折叠行为。
我们表明，决定单结构域或多结构域折叠行为的因素之一是天然接触能量的分散性。因此，我们研究了经过优化以具有与全局能量最小值相同的天然构象但具有不同天然接触能量分散性的序列的折叠情况。我们的结果表明，在天然构象稳定的条件下，折叠性能最佳的蛋白质是那些天然接触能量异质性较小的蛋白质。对于它们来说，折叠转变是全或无的。另一方面，天然接触能量异质性较大的蛋白质具有更渐进的多结构域折叠转变，并且折叠成稳定天然构象的速度比那些天然接触能量分散性小的蛋白质要慢得多。
