Modeling and dynamics of biomolecules on cellular scales

细胞尺度上生物分子的建模和动力学

• 批准号: 9899820
• 负责人: Michael Feig
• 金额: $ 37.74万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899820
• 关键词: Affect; Biochemistry; Biological; Biological Process; Biology; Cells; Communities; Complex; Computer Simulation; Computer software; Crowding; Cryoelectron Microscopy; DNA; DNA Repair; DNA-Directed RNA Polymerase; Data; Development; Disease; Drug Design; Environment; Functional disorder; Genetic Transcription; Malignant Neoplasms; Membrane Proteins; Methods; Mismatch Repair; Modeling; Molecular; Molecular Biology; Nucleic Acids; Play; Proteins; Research; Resolution; Structure; Systems Biology; Therapeutic Intervention; improved; molecular dynamics; molecular scale; protein structure; restraint; single molecule; structural biology; targeted treatment

PROJECT SUMMARY Understanding biology and disease requires a full connection from molecular scales, at which the fundamental biochemistry takes place, to cellular scales, where biological function (or dysfunction) is realized. Structural and molecular biology have long-focused on the molecular levels whereas systems biology emphasizes the cellular scale. The key challenge is now how to connect between these scales to gain a comprehensive understanding of complex diseases and pave the way to rational drug design at the whole-cell level. Computer simulations play a key role in this effort as they allow the modeling of biomolecules at different scales and the subsequent study of their dynamics to connect structure with function. The Feig lab focuses on the development and application of molecular dynamics and multi- scale methods for the high-resolution modeling of proteins and nucleic acids, the mechanistic analysis of fundamental biological processes such as transcription and DNA repair, and studies of biomolecules under crowded cellular environments. Future research focuses on improving protein structure refinement methods to achieve near-experimental accuracy, either de novo or in combination with high-resolution cryo EM data, improve the prediction of membrane protein structures, and develop methods for the high- resolution modeling of chromosomal DNA using experimental restraints from Hi-C data. Mechanistic studies of transcription by RNA polymerase and DNA mismatch repair initiation by MutS will be expanded to more realistic biological contexts and studies of crowded cellular environments will be continued to understand how single molecule dynamics and function is affected by the cellular environment. Finally, multi-scale methods that can bridge from molecular to cellular scales will be developed and implemented in community software.

项目总结