Impact of lymphoma-linked Asn11Tyr point mutation on the interaction between Bcl-2 and a BH3 mimetic: Insights from molecular dynamics simulation.,Chemical Biology & Drug Design

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Impact of lymphoma-linked Asn11Tyr point mutation on the interaction between Bcl-2 and a BH3 mimetic: Insights from molecular dynamics simulation.
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-02-06 , DOI: 10.1111/cbdd.13653
Khushboo Singh ₁ , James M Briggs ₁

Affiliation

Frequent mutations in the Bcl-2 anti-apoptotic protein are often implicated in diffuse large B-cell lymphoma (DLBCL), a disease profoundly resistant to drugs. Bcl-2-competitive inhibitors, "BH3 mimetics," activate apoptosis by interfering with the interactions between pro-apoptotic BH3 domains and the hydrophobic groove of Bcl-2. The aim of our research is to determine the potential of DLBCL-linked N11Y mutation to facilitate resistance against a "BH3 mimetic" using molecular dynamics simulation. Binding free energy calculations suggest a significant decrease in the binding affinity in the mutant model. In-depth analysis of the models using residue interaction network, dynamic cross-correlation, and free energy landscape approaches reveal that the mutation modifies the conformations of key residues, thereby altering the shape of the hydrophobic groove. This subsequently changes the ligand orientation and counteracts the phenomenon of LB region unwinding, a crucial event observed in the wild-type model. Lowest frequency motions captured by principal component analysis reflect the stretching of the groove for efficient ligand accommodation in the wild-type complex but not in the mutant model. This is the first in silico study that unravels the mechanism of drug resistance induced by a Bcl-2 mutation, which could be of great relevance while designing and tailoring therapeutics.

中文翻译：

淋巴瘤相关的Asn11Tyr点突变对Bcl-2和BH3模拟物之间相互作用的影响：分子动力学模拟的见解。

Bcl-2抗凋亡蛋白中的频繁突变通常与弥漫性大B细胞淋巴瘤（DLBCL）有关，这种疾病对药物具有很强的抵抗力。Bcl-2竞争性抑制剂“ BH3模拟物”通过干扰促凋亡BH3结构域与Bcl-2疏水沟之间的相互作用来激活细胞凋亡。我们研究的目的是使用分子动力学模拟确定与DLBCL连锁的N11Y突变促进“ BH3拟态”抗性的潜力。结合自由能的计算表明突变模型中结合亲和力的显着降低。使用残基相互作用网络，动态互相关和自由能景观方法对模型进行深入分析后发现，该突变会修饰关键残基的构象，从而改变疏水槽的形状。随后，这会改变配体的方向并抵消LB区解开现象，这是在野生型模型中观察到的关键事件。通过主成分分析捕获的最低频率运动反映了凹槽的伸展，以有效地在野生型复合体中适应配体，但在突变体模型中却没有。这是第一个计算机模拟研究，揭示了由Bcl-2突变诱导的耐药性机制，这在设计和定制治疗方案时可能具有重大意义。通过主成分分析捕获的最低频率运动反映了凹槽的伸展，以有效地在野生型复合体中适应配体，但在突变体模型中却没有。这是第一个计算机模拟研究，揭示了由Bcl-2突变诱导的耐药性机制，这在设计和定制治疗方案时可能具有重大意义。通过主成分分析捕获的最低频率运动反映了凹槽的伸展，以有效地在野生型复合体中适应配体，但在突变体模型中却没有。这是第一个计算机模拟研究，揭示了由Bcl-2突变引起的耐药性机制，这在设计和定制治疗方案时可能具有重大意义。

更新日期：2020-02-06

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