Most foldable protein sequences adopt only a single native fold. Recent protein design studies have, however, created protein sequences which fold into different structures apon changes of environment, or single point mutation, the best characterized example being the switch between the folds of the GA and GB binding domains of streptococcal protein G. To obtain further insight into the design of sequences which can switch folds, we have used a computational model for the fitness landscape of a single fold, built from the observed sequence variation of protein homologues. We have recently shown that such coevolutionary models can be used to design novel foldable sequences. By appropriately combining two of these models to describe the joint fitness landscape of GA and GB, we are able to describe the propensity of a given sequence for each of the two folds. We have successfully tested the combined model against the known series of designed GA/GB hybrids. Using Monte Carlo simulations on this landscape, we are able to identify pathways of mutations connecting the two folds. In the absence of a requirement for domain stability, the most frequent paths go via sequences in which neither domain is stably folded, reminiscent of the propensity for certain intrinsically disordered proteins to fold into different structures according to context. Even if the folded state is required to be stable, we find that there is nonetheless still a wide range of sequences which are close to the transition region and therefore likely fold switches, consistent with recent estimates that fold switching may be more widespread than had been thought.

中文翻译：

---

探索蛋白质折叠之间的桥梁的序列适合度景观

大多数可折叠的蛋白质序列仅采用单个天然折叠。然而，最近的蛋白质设计研究已经创建了折叠成不同结构的蛋白质序列，以响应环境变化或单点突变，最典型的例子是链球菌蛋白G的GA和GB结合结构域之间的转换。为了进一步了解可以转换折叠的序列的设计，我们根据观察到的蛋白质同源物的序列变化建立了单折叠适应度的计算模型。我们最近显示，此类协同进化模型可用于设计新颖的可折叠序列。通过适当地组合这两种模型来描述GA和GB的联合适应度格局，我们能够描述两个折叠中每个折叠的给定序列的倾向。我们已经针对已知系列的GA / GB混合动力车成功测试了组合模型。在此情况下使用蒙特卡洛模拟，我们能够确定连接两个折叠的突变途径。在不需要结构域稳定性的情况下，最常见的路径是经过序列，其中两个结构域都不会稳定折叠，这让人想起某些内在无序的蛋白质根据上下文折叠成不同结构的倾向。即使要求折叠状态是稳定的，我们仍然发现仍然存在着大范围的序列，这些序列靠近过渡区域，因此可能发生折叠开关，