On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation
On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation
复制标题
DOI：
10.1021/acs.jpcb.8b03708
复制
发表时间：
2018-08-02
影响因子：
3.3
通讯作者：
Pipolo, Silvio
中科院分区：
文献类型：
--
作者：
Galamba, N.;Pipolo, Silvio
蛋白质聚集与多种疾病相关，包括阿尔茨海默病和帕金森病以及镰状细胞病（SCD）。从分子的角度来看，蛋白质聚集取决于由水介导的静电和疏水相互作用的复杂平衡。这种平衡的重要性的一个令人印象深刻的表现涉及人类血红蛋白（HbA）突变体HbS（镰状细胞Hb），其中HbA β链第6位的单个取代（从谷氨酸到缬氨酸）导致脱氧HbS（脱氧HbS）聚合，导致SCD。据信，HbS聚合通过由形成HbS纤维（均质成核）引发的双重成核机制发生，随后是纤维生长。此外，有人提出，均质成核通过两步机制进行，其中亚稳致密团簇起成核前体的作用。因此，阻碍或延迟这些前体的形成可能代表一种潜在的SCD治疗途径。在这里，我们研究，通过分子动力学，结合自由能和蛋白质-蛋白质接触参与脱氧-HbS二聚体聚集和稳定化过程。结合自由能为-14.0 +/-1千卡/摩尔，估计从平均力的一维势。蛋白质相互作用分析表明静电作用和货车范德华力对HbS的聚集起重要作用。对于前者，我们的研究结果表明，聚集在很大程度上有利于形成盐桥（SB），主要是，赖氨酸谷氨酸，赖氨酸天冬氨酸，和HemeLys SB，这超过了静电排斥涉及类似的残基。因此，我们的研究结果表明，一个潜在的抗刺药物可能是一个有能力削弱或阻碍羧酸盐和铵基团之间的一些SB的形成。
Protein aggregation is associated with various diseases, including Alzheimer and Parkinson as well as sickle cell disease (SCD). From a molecular point of view, protein aggregation depends on a complex balance of electrostatic and hydrophobic interactions mediated by water. An impressive manifestation of the importance of this balance concerns the human hemoglobin (HbA) mutant, HbS (sickle cell Hb), where a single substitution at the 6th position of HbA beta-chains, from glutamic acid to valine, causes the polymerization of deoxygenated HbS (deoxy-HbS), responsible for SCD. HbS polymerization is believed to occur via a double nucleation mechanism initiated by the formation of HbS fibers (homogeneous nucleation), followed by fiber growth. Furthermore, it was proposed that homogeneous nucleation proceeds through a two-step mechanism, where metastable dense clusters play the role of nucleation precursors. Thus, hindering or delaying the formation of such precursors could represent a potential SCD therapeutic route. Here, we study, through molecular dynamics, the binding free energy and protein protein contacts involved in the deoxy-HbS dimer aggregation and stabilization process. A binding free energy of similar to-14.0 +/- 1 kcal/mol is estimated from a one-dimensional potential of mean force. Analysis of protein protein interactions shows that both electrostatic and van der Waals interactions play an important role on the aggregation of HbS. With respect to the former, our results indicate that aggregation is largely favored by the formation of salt bridges (SB), mostly, Lys Glu, Lys Asp, and HemeLys SB, which outweigh electrostatic repulsions involving similar residues. Thus, our results suggest that a potential antisickling drug could be one with the ability to weaken or hinder the formation of a few SB between carboxylate and ammonium groups.