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Understanding protein folding, evolution and function via molecular simulation

通过分子模拟了解蛋白质折叠、进化和功能

基本信息

批准号：
10919503
负责人：
Robert Best
金额：
$ 99.98万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10919503
关键词：
2019-nCoV Address Affinity Amino Acid Sequence Amyloid Amyloid Fibrils Area Back Base Sequence Cell Nucleus Cells Charge Collaborations Collagen Collagen Fiber Complex Cytoplasmic Granules Data Data Set Dependence Development Disease Energy Transfer Equilibrium Evolution Extracellular Matrix Fluorescence Resonance Energy Transfer Goals Grain Investigation Ions Liquid substance Machine Learning Maps Measurement Membrane Membrane Proteins Methodology Methods Modeling Molecular Molecular Structure Nuclear Proteins Nucleic Acids Organelles Osmotic Pressure Peptide Hydrolases Peptides Phase Property Protein Engineering Proteins Resolution Roentgen Rays Role Route Scanning Set protein Sodium Chloride Structure Temperature Universities Work design ds-DNA experimental study fitness improved interest member models and simulation novel protein aggregation protein complex protein folding protein function protein misfolding simulation single-molecule FRET theories thermostability

项目摘要

The project has addressed the following areas in the past year: 1. Complex coacervation of highly charged intrinsically disordered proteins. Recent work in collaboration with Ben Schuler's single molecule FRET group in Zurich has shown that high affinity disordered complexes of proteins or proteins and nucleic acids of opposite charge may be ubiquitous in cell nuclei. In addition, we have now found that some of these molecules undergo complex coacervation. Using novel multiscale simulation methodology, we are performing all-atom simulations of a complex coacervate of two nuclear proteins in order to elucidate the interactions responsible for stabilizing these phases, and we are also using new experimental data from FRET experiments and osmotic pressure measurements to help refine the force fields for salt bridges in the proteins as well as interactions of the proteins with ions (M. Ivanovic). (1) 2. Development of better coarse-grained models single-stranded nucleic acids for studying their phase separation/complex coacervation. We have successfully developed a coarse grained model for dsDNA for modeling its role in coacervation. We are now extending this to single stranded nucleic acids. For the purpose of developing better single-stranded nucleic acid models, we are using single-molecule FRET data and small-angle X-ray scattering data to do a force-balance optimization of the force-field. We are currently extending this model to include sequence-specific effects as well as back-mapping to atomistic simulations in a multiscale approach. (K. Lebold) 3. Development of transferable sequence-specific models for liquid-liquid phase separation (LLPS) of intrinsically disordered proteins. We had used a FRET data set on a set of proteins with diverse sequences collected under identical conditions in the Schuler lab to further refine our existing potential, resulting in significant improvements. Because coarse-grained models are necessarily a function of the experimental conditions, we are working to include such effects, in particular temperature as well as cosolvent or Hofmeister effects. (T. Dannenhoffer-Lafage) 4. Sequence dependence of co-phase separation of proteins. In cells, membraneless organelles do not simply consist of a single macromolecular component (or two, in the case of complex coacervation), but likely involve many different molecules. As a starting point for understanding the relative affinity one protein for a coacervate formed by another, we are collaborating with Tuomas Knowles at the University of Cambridge to develop a high-throughput sequence-scanning methodology, which we will use in conjunction with coarse-grained simulations to study this problem (2). (L. Good) 5. Inclusion of secondary structure in coarse-grained models. A common deficiency of many simple coarse grained models (such as single-bead models used for phase separation) as well as higher resolution coarse-grained models is the ability to form secondary structure based on sequence rather than as an input parameter of the simulation. We are developing sequence-specific model to capture secondary structure in coarse-grained models that will allow them to better describe transient secondary structure formation in disordered proteins, as well as formation of more extended secondary structure such as amyloids (R. Best). 6. Using sequence-based energy functions to describe protein fitness landscapes and for protein design. We have shown that it is possible to design novel foldable protein sequences using coevolutionary models. Most recently we have found that we can achieve increased thermostability via this route (2). We are also looking to develop similar ideas to identify proteins which naturally switch folds (such as RfaH), using sequence information. Separately, we are exploring the use of machine learning to predict fitness landscapes for proteins of any given structure; we are also exploring the ability of such models to capture the mechanism of allosteric transitions (L. Frechette, D. Wang). 7. Modelling properties of the extracellular matrix using coarse-grained models. We have recently started developing bottom up coarse-grained simulation models to describe the extracellular matrix and how they are related to its underlying molecular structure. We have initially focused on developing accurate atomistic models for collagen, and validating them against the available data from NMR and small angle X-ray scattering; we are extending this to coarse-grained models that will allow the investigation of packing of tropocollagen in collagen fibers. (G. Pantelopulos). 8. We are working in collaboration with Steve Vogel to understand the mechanisms in certain fluorescent proteins that allow coherent energy transfer via models parameterized from molecular simulations. (G. Taumoefolau). Group members or jointly supervised external collaborators involved in each project are listed at the end of each section.

该计划在过去一年处理了以下范畴：

项目成果

期刊论文数量（76）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The ribosome modulates folding inside the ribosomal exit tunnel.

DOI：
10.1038/s42003-021-02055-8
发表时间：
2021-05-05
期刊：
Communications biology
影响因子：
5.9
作者：
Wruck F;Tian P;Kudva R;Best RB;von Heijne G;Tans SJ;Katranidis A
通讯作者：
Katranidis A

Probing the Action of Chemical Denaturant on an Intrinsically Disordered Protein by Simulation and Experiment.

DOI：
10.1021/jacs.6b05443
发表时间：
2016-09-14
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Zheng W;Borgia A;Buholzer K;Grishaev A;Schuler B;Best RB
通讯作者：
Best RB

Consistent View of Polypeptide Chain Expansion in Chemical Denaturants from Multiple Experimental Methods.

DOI：
10.1021/jacs.6b05917
发表时间：
2016-09-14
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Borgia A;Zheng W;Buholzer K;Borgia MB;Schüler A;Hofmann H;Soranno A;Nettels D;Gast K;Grishaev A;Best RB;Schuler B
通讯作者：
Schuler B

Analysis of Molecular Dynamics Simulations of Protein Folding.

DOI：
10.1007/978-1-0716-1716-8_17
发表时间：
2022-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Best, Robert B
通讯作者：
Best, Robert B

Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.

多个脂质结合位点决定 PH 结构域对含磷酸肌醇膜的亲和力。

DOI：
10.1126/sciadv.aay5736
发表时间：
2020
期刊：
Science advances
影响因子：
13.6
作者：
Yamamoto,Eiji;Domański,Jan;Naughton,FionaB;Best,RobertB;Kalli,AntreasC;Stansfeld,PhillipJ;Sansom,MarkSP
通讯作者：
Sansom,MarkSP