Department of Biochemistry and Structural Biology, Lund University, Lund, Sweden.
Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden.
Proteins. 2018 Jul;86(7):790-801. doi: 10.1002/prot.25516. Epub 2018 May 6.
The coiled coil structural motif consists of alpha helices supercoiling around each other to form staggered knobs-into-holes packing. Such structures are deceptively simple, especially as they often can be described with parametric equations, but are known to exist in various conformations. Even the simplest systems, consisting of 2 monomers, can assemble into a wide range of states. They can form canonical as well as noncanonical coiled coils, be parallel or antiparallel, where helices associate with different degrees of shift, tilt, and rotation. Here, we investigate the energy landscape of heterodimeric coiled coils by carrying out de novo folding simulations starting from amino acid sequence. We folded a diverse set of 22 heterodimers and demonstrate that the approach is capable of identifying the atomic details in the experimental structure in the majority of cases. Our methodology also enables exploration of alternative states that can be accessible in solution beyond the experimentally determined structure. For many systems, we observe folding energy landscapes with multiple energy minima and several isoenergetic states. By comparing coiled coils from single domains and those extracted from larger proteins, we find that standalone coiled coils have deeper energy wells at the experimentally determined conformation. By folding the competing homodimeric states in addition to the heterodimers, we observe that the structural specificity towards the heteromeric state is often small. Taken together, our results demonstrate that de novo folding simulations can be a powerful tool to characterize structural specificity of coiled coils when coupled to assessment of energy landscapes.
螺旋线圈结构基元由彼此缠绕的α 螺旋组成，形成交错的旋钮-孔包装。这些结构看起来很简单，尤其是它们通常可以用参数方程来描述，但已知它们存在于各种构象中。即使是由 2 个单体组成的最简单的系统，也可以组装成多种状态。它们可以形成规范和非规范的螺旋线圈，可以是平行的或反平行的，其中螺旋以不同程度的位移、倾斜和旋转进行关联。在这里，我们通过从头开始进行氨基酸序列的折叠模拟来研究杂二聚体螺旋线圈的能量景观。我们折叠了一组不同的 22 个杂二聚体，并证明该方法能够在大多数情况下识别实验结构中的原子细节。我们的方法还能够探索在实验确定的结构之外的溶液中可达到的替代状态。对于许多系统，我们观察到具有多个能量最小值和几个等能量状态的折叠能量景观。通过比较来自单个结构域的螺旋线圈和从更大蛋白质中提取的螺旋线圈，我们发现独立的螺旋线圈在实验确定的构象下具有更深的能量阱。通过折叠除杂二聚体外的竞争同型二聚体状态，我们观察到对杂合状态的结构特异性通常很小。总之，我们的结果表明，当与能量景观评估相结合时，从头开始的折叠模拟可以成为表征螺旋线圈结构特异性的有力工具。
