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{"title":"Molecular Modeling is an Enabling Approach to Complement and Enhance Channelopathy Research.","authors":"Michael T Zimmermann","doi":"10.1002/cphy.c190047","DOIUrl":null,"url":null,"abstract":"<p><p>Hundreds of human membrane proteins form channels that transport necessary ions and compounds, including drugs and metabolites, yet details of their normal function or how function is altered by genetic variants to cause diseases are often unknown. Without this knowledge, researchers are less equipped to develop approaches to diagnose and treat channelopathies. High-resolution computational approaches such as molecular modeling enable researchers to investigate channelopathy protein function, facilitate detailed hypothesis generation, and produce data that is difficult to gather experimentally. Molecular modeling can be tailored to each physiologic context that a protein may act within, some of which may currently be difficult or impossible to assay experimentally. Because many genomic variants are observed in channelopathy proteins from high-throughput sequencing studies, methods with mechanistic value are needed to interpret their effects. The eminent field of structural bioinformatics integrates techniques from multiple disciplines including molecular modeling, computational chemistry, biophysics, and biochemistry, to develop mechanistic hypotheses and enhance the information available for understanding function. Molecular modeling and simulation access 3D and time-dependent information, not currently predictable from sequence. Thus, molecular modeling is valuable for increasing the resolution with which the natural function of protein channels can be investigated, and for interpreting how genomic variants alter them to produce physiologic changes that manifest as channelopathies. © 2022 American Physiological Society. Compr Physiol 12:3141-3166, 2022.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 2","pages":"3141-3166"},"PeriodicalIF":4.2000,"publicationDate":"2022-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Comprehensive Physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cphy.c190047","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
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Abstract
Hundreds of human membrane proteins form channels that transport necessary ions and compounds, including drugs and metabolites, yet details of their normal function or how function is altered by genetic variants to cause diseases are often unknown. Without this knowledge, researchers are less equipped to develop approaches to diagnose and treat channelopathies. High-resolution computational approaches such as molecular modeling enable researchers to investigate channelopathy protein function, facilitate detailed hypothesis generation, and produce data that is difficult to gather experimentally. Molecular modeling can be tailored to each physiologic context that a protein may act within, some of which may currently be difficult or impossible to assay experimentally. Because many genomic variants are observed in channelopathy proteins from high-throughput sequencing studies, methods with mechanistic value are needed to interpret their effects. The eminent field of structural bioinformatics integrates techniques from multiple disciplines including molecular modeling, computational chemistry, biophysics, and biochemistry, to develop mechanistic hypotheses and enhance the information available for understanding function. Molecular modeling and simulation access 3D and time-dependent information, not currently predictable from sequence. Thus, molecular modeling is valuable for increasing the resolution with which the natural function of protein channels can be investigated, and for interpreting how genomic variants alter them to produce physiologic changes that manifest as channelopathies. © 2022 American Physiological Society. Compr Physiol 12:3141-3166, 2022.
分子模型是补充和加强通道病研究的一种有利方法。
数以百计的人体膜蛋白形成通道,运输必要的离子和化合物,包括药物和代谢物,但其正常功能的细节或功能如何被基因变异改变而导致疾病,往往是未知的。没有这方面的知识,研究人员就无法开发出诊断和治疗经络病变的方法。高分辨率的计算方法,如分子建模,使研究人员能够研究通道病蛋白的功能,促进详细的假设生成,并产生难以通过实验收集的数据。分子模型可以根据蛋白质可能发挥作用的每个生理环境进行定制,其中一些可能目前难以或不可能通过实验进行分析。由于在高通量测序研究中,在通道病蛋白中观察到许多基因组变异,因此需要具有机制价值的方法来解释其影响。结构生物信息学的杰出领域整合了包括分子建模、计算化学、生物物理学和生物化学在内的多个学科的技术,以发展机制假设并增强可用于理解功能的信息。分子建模和模拟访问三维和时间相关的信息,目前不能从序列预测。因此,分子模型对于提高研究蛋白质通道自然功能的分辨率,以及解释基因组变异如何改变它们以产生表现为通道病变的生理变化是有价值的。©2022美国生理学会。中国生物医学工程学报(英文版),2016。
本文章由计算机程序翻译,如有差异,请以英文原文为准。