MutDock: A computational docking approach for fixed-backbone protein scaffold design.
MutDock: A computational docking approach for fixed-backbone protein scaffold design.
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DOI：
10.3389/fmolb.2022.933400
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发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
--
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尽管抗体作为治疗性结合蛋白取得了成功，但它们仍然面临着生产和设计方面的挑战。为了克服这些问题，已经开发了较小尺寸的替代结合支架。这些替代支架的一个子集通过对一组表面驻留的突变来识别目标分子，这不会改变它们的骨干结构。虽然针对目标表位的抗体的计算设计已经进行了深入的探索，但替代支架的计算设计还没有完成。通常用于结合蛋白质（包括抗体）的dock-and- mutation方法是有限的，因为它使用支架的恒定序列和结构表示。将固定骨架支架与不同的表面氨基酸组对接，增加了识别更好的起始姿势的机会，这些姿势可以通过随后的突变得到改善。在这项工作中，我们开发了MutDock，这是一种新的计算方法，通过识别最小数量的氢键，同时对接和突变固定骨架支架，以结合目标表位。该方法大致分为两个步骤。第一步使用支架残基和相容表位原子的氢键形成区域的成对距离排列。这一步考虑了原生和突变的支架残基旋转体。第二步改变碰撞可变界面残基和热力学不利残基以产生额外的强相互作用。MutDock用于将两个支架（即词性体和DARPins）与随机选择的10种抗原进行对接。将对接位姿的能量最小化，并与ZDOCK和HADDOCK的对接位姿的结合能进行比较。MutDock位姿的结合能分别高于ZDOCK位姿和HADDOCK位姿。这项工作有助于发现基于小尺寸固定骨架蛋白支架的新型粘合剂。
Despite the successes of antibodies as therapeutic binding proteins, they still face production and design challenges. Alternative binding scaffolds of smaller size have been developed to overcome these issues. A subset of these alternative scaffolds recognizes target molecules through mutations to a set of surface resides, which does not alter their backbone structures. While the computational design of antibodies for target epitopes has been explored in depth, the same has not been done for alternative scaffolds. The commonly used dock-and-mutate approach for binding proteins, including antibodies, is limited because it uses a constant sequence and structure representation of the scaffold. Docking fixed-backbone scaffolds with a varied group of surface amino acids increases the chances of identifying superior starting poses that can be improved with subsequent mutations. In this work, we have developed MutDock, a novel computational approach that simultaneously docks and mutates fixed backbone scaffolds for binding a target epitope by identifying a minimum number of hydrogen bonds. The approach is broadly divided into two steps. The first step uses pairwise distance alignment of hydrogen bond-forming areas of scaffold residues and compatible epitope atoms. This step considers both native and mutated rotamers of scaffold residues. The second step mutates clashing variable interface residues and thermodynamically unfavorable residues to create additional strong interactions. MutDock was used to dock two scaffolds, namely, Affibodies and DARPins, with ten randomly selected antigens. The energies of the docked poses were minimized and binding energies were compared with docked poses from ZDOCK and HADDOCK. The top MutDock poses consisted of higher and comparable binding energies than the top ZDOCK and HADDOCK poses, respectively. This work contributes to the discovery of novel binders based on smaller-sized, fixed-backbone protein scaffolds.
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影响因子：
5
作者：
Honorato RV;Koukos PI;Jiménez-García B;Tsaregorodtsev A;Verlato M;Giachetti A;Rosato A;Bonvin AMJJ
通讯作者：
Bonvin AMJJ
影响因子：
4.3
作者：
Adolf-Bryfogle, Jared;Kalyuzhniy, Oleks;Dunbrack, Roland L., Jr.
通讯作者：
Dunbrack, Roland L., Jr.
影响因子：
14.9
作者：
Comeau, SR;Gatchell, DW;Camacho, CJ
通讯作者：
Camacho, CJ
影响因子：
5.6
作者：
Fleishman, Sarel J.;Corn, Jacob E.;Strauch, Eva-Maria;Whitehead, Timothy A.;Karanicolas, John;Baker, David
通讯作者：
Baker, David
影响因子：
5.3
作者：
Ducancel, Frederic;Muller, Bruno H.
通讯作者：
Muller, Bruno H.