Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints.
Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints.
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DOI：
10.1371/journal.pone.0154811
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Meiler J
中科院分区：
文献类型：
--
作者：
Finn JA;Koehler Leman J;Willis JR;Cisneros A 3rd;Crowe JE Jr;Meiler J
结构限制甚至存在于抗体的最序列多样性部分，互补决定区（CDR）环中。先前的研究确定了为六个CDR环中的五个定义规范结构的稳健规则，然而重链CDR 3（HCDR 3）违背了标准分类尝试。HCDR 3环可以被细分为称为“躯干”和“头部”结构域的两个结构域，并且已经鉴定了两个主要的典型躯干结构家族;更普遍的“凸出”躯干和不太常见的“非凸出”躯干。在本研究中，我们发现，罗塞塔环建模的28个基准凸起的HCDR 3环与知识为基础的结构限制，从现有的抗体晶体结构中的PDB的改进。这些约束限制了Rosetta在躯干域中搜索的采样空间，将这些残基的φ和矩形限制为实验观察到的构象。这些限制在Rosetta中的应用导致更多的天然样结构采样和改进的天然样HCDR 3模型的基于评分的分化，显著提高了我们对抗体HCDR 3环建模的能力。
Structural restrictions are present even in the most sequence diverse portions of antibodies, the complementary determining region (CDR) loops. Previous studies identified robust rules that define canonical structures for five of the six CDR loops, however the heavy chain CDR 3 (HCDR3) defies standard classification attempts. The HCDR3 loop can be subdivided into two domains referred to as the “torso” and the “head” domains and two major families of canonical torso structures have been identified; the more prevalent “bulged” and less frequent “non-bulged” torsos. In the present study, we found that Rosetta loop modeling of 28 benchmark bulged HCDR3 loops is improved with knowledge-based structural restraints developed from available antibody crystal structures in the PDB. These restraints restrict the sampling space Rosetta searches in the torso domain, limiting the φ and ψ angles of these residues to conformations that have been experimentally observed. The application of these restraints in Rosetta result in more native-like structure sampling and improved score-based differentiation of native-like HCDR3 models, significantly improving our ability to model antibody HCDR3 loops.