Dynamic Interplay of Loop Motions Governs the Molecular Level Regulatory Dynamics in Spleen Tyrosine Kinase: Insights from Molecular Dynamics Simulations

被引:0
|
作者
Samanta, Sunanda [1 ]
Sk, Md Fulbabu [1 ,2 ]
Koirala, Suman [1 ]
Kar, Parimal [1 ]
机构
[1] Indian Inst Technol Indore, Dept Biosci & Biomed Engn, Indore 453552, Madhya Pradesh, India
[2] Univ Illinois, Beckman Inst Adv Sci & Technol, Theoret & Computat Biophys Grp, NIH Resource Macromol Modeling & Visualizat, Urbana, IL 61801 USA
来源
JOURNAL OF PHYSICAL CHEMISTRY B | 2024年 / 128卷 / 43期
关键词
STRUCTURAL BASIS; SYK; AMBER; PARAMETERS; INHIBITORS; LANGEVIN; PROTEINS; ACCURACY; ZAP-70; PLAYER;
D O I
10.1021/acs.jpcb.4c03217
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
The spleen tyrosine kinase (Syk) is a key regulator in immune cell signaling and is linked to various mechanisms in cancer and neurodegenerative diseases. Although most computational research on Syk focuses on novel drug design, the molecular-level regulatory dynamics remain unexplored. In this study, we utilized 5 x 1 mu s all-atom molecular dynamics simulations of the Syk kinase domain, examining it in combinations of activation segment phosphorylated/unphosphorylated (at Tyr525, Tyr526) and the "DFG"-Asp protonated/deprotonated (at Asp512) states to investigate conformational variations and regulatory dynamics of various loops and motifs within the kinase domain. Our findings revealed that the formation and disruption of several electrostatic interactions among residues within and near the activation segment likely influenced its dynamics. The protein structure network analysis indicated that the N-terminal and C-terminal anchors were stabilized by connections with the nearby stable helical regions. The P-loop showed conformational variation characterized by movements toward and away from the conserved "HRD"-motif. Additionally, there was a significant correlation between the movement of the beta 3-alpha C loop and the P-loop, which controls the dimensions of the adenine-binding cavity of the C-spine region. Overall, understanding these significant motions of the Syk kinase domain enhances our knowledge of its functional regulatory mechanism and can guide future research.
引用
收藏
页码:10565 / 10580
页数:16
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