Design of Protein Multi-specificity Using an Independent Sequence Search Reduces the Barrier to Low Energy Sequences.
Design of Protein Multi-specificity Using an Independent Sequence Search Reduces the Barrier to Low Energy Sequences.
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DOI：
10.1371/journal.pcbi.1004300
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发表时间：
2015-07
影响因子：
4.3
通讯作者：
Meiler J
中科院分区：
文献类型：
--
作者：
Sevy AM;Jacobs TM;Crowe JE Jr;Meiler J
计算蛋白质设计已经在工程蛋白质的热力学稳定性，结合特异性，或酶活性的“单态”设计（SSD）范例中取得了巨大的成功。另一方面，多特异性设计（MSD）涉及同时考虑多种蛋白质状态的稳定性。我们开发了一种新的MSD算法，我们称之为多特异性设计中的约束收敛（RECON）。该算法允许每个状态在整个设计过程中采用自己的序列，而不是在所有状态上强制执行单个序列。收敛到一个单一的序列是鼓励通过一个递增的收敛约束相应的位置。与在所有状态上强制（约束）相同序列的MSD算法相比，能量景观被简化，这大大加速了搜索。因此，RECON可以很容易地用于具有灵活蛋白质骨架的模拟。我们在两个设计任务上对RECON进行了基准测试。首先，我们设计了来自一个共同的生殖系基因的抗体，针对其不同的目标，以评估生殖系，多特异性序列的恢复。其次，我们设计了“混杂”，多特异性蛋白质对所有的结合伙伴和测量恢复的天然序列。我们表明，RECON是能够有效地恢复天然样，生物相关的序列，在这个不同的蛋白质复合物。设计具有所需活性的新蛋白质的能力一直是计算生物学家的长期目标，即创造具有新的结合活性或增加稳定性的蛋白质。一个更雄心勃勃的目标是多特异性设计，它通过创建具有多个结合伴侣的低能量序列来扩展一般蛋白质设计。我们开发了一种新的多特异性设计算法，可以更有效地为所有复合物找到低能量序列。这种提高的效率使得能够模拟结合配偶体之间的生物学相关运动，例如主链运动和取向转变。我们表明，我们的算法优于现有的方法，并比较预测的低能量序列的序列自然看到通过每个蛋白质的进化。我们发现，该算法能够更准确地表示在生物背景下发现的序列的范围。该方法可用于设计具有结合多个不同伴侣的能力的新蛋白质。
Computational protein design has found great success in engineering proteins for thermodynamic stability, binding specificity, or enzymatic activity in a ‘single state’ design (SSD) paradigm. Multi-specificity design (MSD), on the other hand, involves considering the stability of multiple protein states simultaneously. We have developed a novel MSD algorithm, which we refer to as REstrained CONvergence in multi-specificity design (RECON). The algorithm allows each state to adopt its own sequence throughout the design process rather than enforcing a single sequence on all states. Convergence to a single sequence is encouraged through an incrementally increasing convergence restraint for corresponding positions. Compared to MSD algorithms that enforce (constrain) an identical sequence on all states the energy landscape is simplified, which accelerates the search drastically. As a result, RECON can readily be used in simulations with a flexible protein backbone. We have benchmarked RECON on two design tasks. First, we designed antibodies derived from a common germline gene against their diverse targets to assess recovery of the germline, polyspecific sequence. Second, we design “promiscuous”, polyspecific proteins against all binding partners and measure recovery of the native sequence. We show that RECON is able to efficiently recover native-like, biologically relevant sequences in this diverse set of protein complexes. The ability to design a new protein with a desired activity has been a longstanding goal of computational biologists, to create proteins with new binding activity or increased stability. An even more ambitious goal is multi-specificity design, which extends general protein design by creating a sequence that has low energy with multiple binding partners. We have developed a new algorithm for multi-specificity design that more efficiently finds a low energy sequence for all complexes. This increased efficiency enables simulation of biologically relevant motion between binding partners, such as backbone movement and shifts in orientation. We show that our algorithm outperforms existing approaches, and compare the predicted low energy sequences to the sequences naturally seen through evolution of each protein. We find that this algorithm is able to more accurately represent the scope of sequences that are found in biological contexts. This method can be applied to design new proteins with the ability to bind multiple distinct partners.
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DOI：
10.1073/pnas.0506124102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Bolon, DN;Grant, RA;Sauer, RT
通讯作者：
Sauer, RT
影响因子：
64.8
作者：
Ashworth, Justin;Havranek, James J.;Baker, David
通讯作者：
Baker, David
影响因子：
5.8
作者：
Fromer, Menachem;Yanover, Chen;Linial, Michal
通讯作者：
Linial, Michal
DOI：
10.1073/pnas.97.19.10383
发表时间：
2000-09-12
影响因子：
11.1
作者：
Kuhlman, B;Baker, D
通讯作者：
Baker, D
影响因子：
64.8
作者：
Grigoryan, Gevorg;Reinke, Aaron W.;Keating, Amy E.
通讯作者：
Keating, Amy E.