Unraveling the Microscopic Mechanism of Molecular Ion Interaction with Monoclonal Antibodies: Impact on Protein Aggregation
Unraveling the Microscopic Mechanism of Molecular Ion Interaction with Monoclonal Antibodies: Impact on Protein Aggregation
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DOI：
10.1021/acs.molpharmaceut.3c00963
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发表时间：
2024-02-12
影响因子：
4.9
通讯作者：
Bresme，Fernando
中科院分区：
文献类型：
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作者：
Saurabh，Suman;Zhang，Qinkun;Bresme，Fernando
理解和预测蛋白质聚集是加速蛋白质治疗药物开发的主要挑战之一。除了维持溶液pH值外，缓冲液还影响单克隆抗体（mAb）在溶液中的聚集和聚集机制，因为后者取决于蛋白质电荷。分子水平的洞察力对于理解缓冲液-mAb相互作用和mAb聚集之间的关系是必要的。在这里，我们使用全原子分子动力学模拟研究磷酸盐（Phos）和柠檬酸盐（Cit）缓冲液离子与mAb COE 3的Fab和Fc结构域的相互作用。我们证明thatPhosandCitions功能结合机制，与蛋白质是非常不同的那些以前报道的组氨酸（His）。这些差异反映在独特的离子-蛋白结合模式和缓冲液分子从mAb表面的吸附/解吸动力学中，并导致这些缓冲液物质对mAb聚集的不同影响。虽然His对蛋白质表面上的疏水性氨基酸显示出显着的亲和力，PhosandCitions优先结合带电氨基酸。我们还表明，PhosandCitanions提供了邻近蛋白质中碱性氨基酸之间的桥接接触。讨论了这种接触的影响及其与治疗制剂中mAb聚集的联系。
Understanding and predicting protein aggregation represents one of the major challenges in accelerating the pharmaceutical development of protein therapeutics. In addition to maintaining the solution pH, buffers influence both monoclonal antibody (mAb) aggregation in solution and the aggregation mechanisms since the latter depend on the protein charge. Molecular-level insight is necessary to understand the relationship between the buffer–mAb interaction and mAb aggregation. Here, we use all-atom molecular dynamics simulations to investigate the interaction of phosphate (Phos) and citrate (Cit) buffer ions with the Fab and Fc domains of mAb COE3. We demonstrate thatPhosandCitions feature binding mechanisms, with the protein that are very different from those reported previously for histidine(His). These differences are reflected in distinctive ion-protein binding modes and adsorption/desorption kinetics of the buffer molecules from the mAb surface and result in dissimilar effects of these buffer species on mAb aggregation. WhileHisshows significant affinity toward hydrophobic amino acids on the protein surface,PhosandCitions preferentially bind to charged amino acids. We also show thatPhosandCitanions provide bridging contacts between basic amino acids in neighboring proteins. The implications of such contacts and their connection to mAb aggregation in therapeutic formulations are discussed.