Proteins with similar structures are generally assumed to arise from similar sequences. However, there are more cases than not where this is not true. The dogma is that sequence determines structure; how, then, can very different sequences fold to the same structure? Here, we employ high temperature unfolding simulations to probe the pathways and specific interactions that direct the folding and unfolding of the SH3 domain. The SH3 metafold in the Dynameomics Database consists of 753 proteins with the same structure, but varied sequences and functions. To investigate the relationship between sequence and structure, we selected 17 targets from the SH3 metafold with high sequence variability. Six unfolding simulations were performed for each target, transition states were identified, revealing two general folding/unfolding pathways at the transition state. Transition states were also expressed as mathematical graphs of connected chemical nodes, and it was found that three positions within the structure, independent of sequence, were consistently more connected within the graph than any other nearby positions in the sequence. These positions represent a hub connecting different portions of the structure. Multiple sequence alignment and covariation analyses also revealed certain positions that were more conserved due to packing constraints and stabilizing long‐range contacts. This study demonstrates that members of the SH3 domain with different sequences can unfold through two main pathways, but certain characteristics are conserved regardless of the sequence or unfolding pathway. While sequence determines structure, we show that disparate sequences can provide similar interactions that influence folding and lead to similar structures.

中文翻译：

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SH3域结构同源物展开过渡态的保守模式和相互作用

通常假设具有相似结构的蛋白质来自相似的序列。然而，在很多情况下这不是真的。教条是顺序决定结构；那么，非常不同的序列如何折叠成相同的结构？在这里，我们采用高温展开模拟来探索指导 SH3 域折叠和展开的途径和特定相互作用。Dynameomics 数据库中的 SH3 元折叠由 753 个结构相同但序列和功能不同的蛋白质组成。为了研究序列和结构之间的关系，我们从 SH3 元折叠中选择了 17 个具有高序列变异性的目标。对每个目标进行了六次展开模拟，确定了过渡状态，揭示了过渡态的两种一般折叠/展开途径。过渡态也表示为连接化学节点的数学图，并且发现结构中的三个位置，独立于序列，在图中始终比序列中任何其他附近位置更连接。这些位置代表连接结构不同部分的枢纽。多序列比对和协变分析还揭示了由于包装限制和稳定远程接触而更保守的某些位置。该研究表明，具有不同序列的 SH3 结构域成员可以通过两种主要途径展开，但无论序列或展开途径如何，某些特征都是保守的。顺序决定结构，