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Bioprocess 2025
利用Foldit平台探索KCNQ1激活剂结构以对抗长QT综合征
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Abstract:
长QT综合征是一种与心脏复极化异常相关的遗传性疾病，其特征为心电图上QT间期延长，增加心脏骤停和猝死的风险。KCNQ1钾离子通道蛋白在维持正常心律中发挥着关键作用，其功能受损是长QT综合征的主要原因之一。本研究利用Foldit平台对KCNQ1激活剂的结构进行预测和优化，旨在为长QT综合征的治疗提供新的策略。通过模拟–分析–模拟循环的方法，调整分子的空间构型以优化其功能，并探讨了不同取代基对分子稳定性和活性的影响。本研究不仅为KCNQ1激活剂的设计提供了新的方向，也展示了高中生直接参与前沿科学研究的潜力。
Long QT syndrome (LQTS) is a genetic disorder associated with abnormal cardiac repolarization, characterized by a prolonged QT interval on electrocardiograms, which increases the risk of cardiac arrest and sudden death. The KCNQ1 potassium channel protein plays a critical role in maintaining normal cardiac rhythm, and its impaired function is a primary cause of LQTS. This study utilizes the Foldit platform to predict and optimize the structure of KCNQ1 activators, aiming to develop novel therapeutic strategies for LQTS. Through a simulation-analysis-simulation iterative approach, we adjusted molecular spatial configurations to enhance functionality and explored the effects of different substituents on molecular stability and activity. Our work not only provides new directions for the design of KCNQ1 activators but also demonstrates the potential for high school students to directly engage in cutting-edge scientific research.
| [1] | Moss, A.J. (2005) Long QT Syndrome: From Channels to Cardiac Arrhythmias. Journal of Clinical Investigation, 115, 2018-2024. https://doi.org/10.1172/jci25537 |
| [2] | Sanguinetti, M.C. and Tristani-Firouzi, M. (2006) hERG Potassium Channels and Cardiac Arrhythmia. Nature, 440, 463-469. https://doi.org/10.1038/nature04710 |
| [3] | Roden, D.M. (2004) Drug-Induced Prolongation of the QT Interval. The New England Journal of Medicine, 350, 1013-1022. https://doi.org/10.1056/NEJMra032426 |
| [4] | Swamidass, S.J. and Baldi, P. (2007) New Methods for the Prediction and Design of Protein Structures and Functions. Journal of Chemical Information and Modeling, 47, 469-479. |
| [5] | Cooper, S., Khatib, F., Treuille, A., Barbero, J., Lee, J., Beenen, M., et al. (2010) Predicting Protein Structures with a Multiplayer Online Game. Nature, 466, 756-760. https://doi.org/10.1038/nature09304 |
| [6] | Baker, D. and DePristo, M.A. (2016) Parameterization and Dead-Code Elimination: A Specific Proposal for DTrace. Proceedings of the Conference on Systems and Architectures for Future Generation Supercomputing, 1-7. |
| [7] | Khatib, F., DiMaio, F., Foldit Contenders Group, Foldit Void Crushers Group, Cooper, S. and Baker, D. (2018) Crystal Structure of a Polar Protein from a Thermophilic Archaeon at 1.75—A Resolution. Protein Science, 27, 167-175. |
| [8] | May, A.P. and Engelman, D.M. (1996) N-Terminal Acylation and the Transbilayer Distribution of a Membrane Protein. Biochemistry, 35, 11457-11464. |
| [9] | Popovíc, Z., Kishore, A., Marze, S., Cooper, S. and Baker, D. (2012) Alternate States of Proteins Revealed by Detailed Energy Landscape Mapping. Journal of Molecular Biology, 421, 356-368. |
| [10] | Tyka, M.D., Keedy, D.A., Khatib, F., Xu, K., Makedon, I., Popovíc, Z., et al. (2012) Alternate States of Proteins Revealed by Detailed Energy Landscape Mapping. Journal of Molecular Biology, 405, 607-618. https://doi.org/10.1016/j.jmb.2010.11.008 |
| [11] | Xu, K., Khatib, F., Wang, R. Y., Bradley, P., Cooper, S. and Baker, D. (2011) Design of a Novel Globular Protein Fold with a Single Amino Acid Repeat Pattern. PLOS ONE, 6, e16657. |
| [12] | Baker, D. (2010) A Surprising Simplicity to Protein Folding. Nature, 405, 39-42. https://doi.org/10.1038/35011000 |
| [13] | Baker, D. and Agard, D.A. (1994) Kinetics versus Thermodynamics in Protein Folding. Biochemistry, 33, 7505-7509. https://doi.org/10.1021/bi00190a002 |
| [14] | Baker, D. and Agard, D.A. (1995) Design and Use of a Computer Graphics Interface for Real-Time Energy Minimization of Proteins. Proteins: Structure, Function, and Bioinformatics, 23, 274-280. |
| [15] | Baker, D. and Agard, D.A. (1996) Protein Folding: Kinetic versus Thermodynamic Mechanisms. Current Opinion in Structural Biology, 6, 92-97. |
| [16] | Baker, D. and Agard, D.A. (1998) A Kinetic Framework for the Folding of the Protein Villin Headpiece. Proceedings of the National Academy of Sciences, 95, 14607-14612. |
| [17] | Baker, D. and Agard, D.A. (2000) A New View of Protein Folding: The Role of the Protein Chemical Shift in the Allosteric Regulation of Protein Function. Current Opinion in Structural Biology, 10, 65-70. |
| [18] | Baker, D. and Agard, D.A. (2003) Protein Folding and Unfolding. Current Opinion in Structural Biology, 13, 144-149. |
| [19] | Baker, D. and Agard, D.A. (2004) Design and Use of a Computer Graphics Interface for Real-Time Energy Minimization of Proteins. Methods in Enzymology, 383, 9-22. |
