Forces Driving Membrane Protein Folds

驱动膜蛋白折叠的力量

• 批准号: 10551562
• 负责人: Karen G. Fleming
• 金额: $ 39.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551562
• 关键词: Biology; Biophysics; Catalysis; Chemicals; Complement; Computational algorithm; Computer Models; Databases; Disease; Equilibrium; Hydrogen Bonding; Investigation; Knowledge; Lipid Bilayers; Membrane Proteins; Modeling; Molecular; Molecular Conformation; Phospholipids; Physical Chemistry; Protein Conformation; Protein Engineering; Proteins; Research; Solvents; Structure; Therapeutic; Training; Vertebral column; Water; driving force; novel; protein folding; protein misfolding; protein structure; rational design; simulation

Project Summary Understanding how proteins fold is a central quest in biology. Studied for over 50 years, investigations of soluble protein folding have proven invaluable for dissecting the molecular basis of a multitude of diseases. By comparison, folding studies of membrane proteins lag far behind. The knowledge gained from soluble protein studies cannot simply be transferred to inferences about because their solvents are different. The balance of forces encoding a MP embedded in a lipid bilayer must be distinct from that of soluble proteins in water. Our research efforts contribute to filling this key gap in the understanding the physical chemistry of membrane proteins. We will experimentally determine of energetic forces stabilizing membrane proteins along the steeply changing polarity gradient of the phospholipid bilayer interface, quantify backbone hydrogen bond strengths, and expand our repertoire of membrane protein folding models to include those with an a-helical secondary structure. These efforts will be complemented by molecular simulations and other solution biophysics interrogations as needed. Our results have broad ranging impact in the field at large through contributions to information databases used in training computational algorithms and by their incorporation in physically realistic mechanisms for protein folding catalysis by cellular machines.

项目摘要 了解蛋白质如何折叠是生物学的核心探索。研究了50多年 多年来，对可溶性蛋白质折叠的研究已经被证明对于解剖 多种疾病的分子基础。通过比较，膜的折叠研究 蛋白质远远落后于此。从可溶性蛋白质研究中获得的知识不能简单地 被转移到推论，因为他们的溶剂是不同的。收支平衡 编码包埋在脂质双层中的MP的作用力必须与可溶性的不同 水中的蛋白质。 我们的研究努力有助于填补理解物理的这一关键空白 膜蛋白化学。我们将在实验中测定能量 沿着急剧变化的极性梯度稳定膜蛋白 磷脂双层界面，量化主链氢键强度，并扩展 我们的膜蛋白折叠模型包括那些带有a-螺旋的模型 二级结构。这些努力将得到分子模拟和 根据需要进行其他溶液生物物理讯问。 我们的成果通过对以下方面的贡献在整个领域产生了广泛的影响 用于训练计算算法的信息数据库及其 掺入细胞催化蛋白质折叠的物理机制 机器。