CAREER: Mechanistic Investigations of Conformational Activation and Catalysis in Emerging CRISPR-Cas Systems

职业:新兴 CRISPR-Cas 系统中构象激活和催化的机制研究

基本信息

  • 批准号:
    2144823
  • 负责人:
  • 金额:
    $ 65.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Giulia Palermo from the University of California, Riverside, to investigate the molecular mechanisms underlying the catalytic activities of newly emerging CRISPR (clustered regularly interspaced short palindromic repeat)-Cas systems. Inspired by the initial CRISPR-Cas9 gene editing tool, several novel CRISPR-Cas systems have recently been developed that precisely manipulate DNA and RNA in a cell. State-of-the-art of computational methods will be used to determine how these new systems change the chemical composition of DNA bases, cut both strands of the DNA double-helix, and target RNA. The results from this study are expected to aid in the development of novel CRISPR-Cas-based biotechnologies, such as nucleic acid detection and imaging. In addition, the applications of methods development aspects of this project have the potential to extend from the biosciences to fuel production and to the development of drought-resistant crops. This project will integrate with an educational plan that mentors a large cohort of pre-college and undergraduate students, including women and those from underrepresented minority groups. Students will receive their first hands-on experience in program coding and computation, building the technical skills to succeed in the 21st century technological workplace. CRISPR-Cas is an integral part of a bacterial adaptive immune response that has revolutionized life sciences as a genome editing tool. This project will employ advanced computational methods to characterize the mechanisms of conformational activation and catalysis in novel CRISPR-Cas systems, including Cas12a and Cas13a and emerging Cas9-based complexes. Long timescale molecular dynamics (MD) simulations will be combined with a variety of enhanced sampling techniques and free-energy methods to thoroughly investigate the conformational changes of the Cas proteins that prompt nucleic acid cleavages. Mixed quantum mechanics/molecular mechanics (QM/MM) approaches and ab-initio MD will be used to elucidate details of the chemical mechanisms driving the catalysis of nucleic acids, with the potential to enhance catalytic efficiency and guide enzyme design. The computational studies will be coordinated in collaboration with experimentalists to assist with the interpretation of experimental data and enable testable predictions. Overall, this study will help elucidate the biomolecular function of these emergent CRISPR-Cas systems, bridging the gap between understanding molecular mechanisms and engineering applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
该奖项全部或部分由《2021年美国救援计划法案》(公法117-2)资助。有了这个奖项,化学部门的生命过程化学项目资助了加州大学河滨分校的Giulia Palermo博士,研究新出现的CRISPR(聚集规律间隔短回文重复)-Cas系统催化活性的分子机制。受最初的CRISPR-Cas9基因编辑工具的启发,最近开发了几种新的CRISPR-Cas系统,可以精确地操纵细胞中的DNA和RNA。最先进的计算方法将用于确定这些新系统如何改变DNA碱基的化学组成,切割DNA双螺旋的两条链,以及靶向RNA。这项研究的结果有望帮助开发新的基于crispr - cas的生物技术,如核酸检测和成像。此外,这个项目的方法发展方面的应用有可能从生物科学扩展到燃料生产和抗旱作物的发展。该项目将与一项教育计划相结合,该计划将为大批大学预科生和本科生提供指导,其中包括妇女和来自代表性不足的少数群体的学生。学生将获得程序编码和计算方面的第一次实践经验,培养在21世纪技术工作场所取得成功的技术技能。CRISPR-Cas是细菌适应性免疫反应的一个组成部分,作为一种基因组编辑工具,它已经彻底改变了生命科学。该项目将采用先进的计算方法来表征新型CRISPR-Cas系统中的构象激活和催化机制,包括Cas12a和Cas13a以及新兴的基于cas9的复合物。长时间尺度分子动力学(MD)模拟将与各种增强的采样技术和自由能方法相结合,以彻底研究促使核酸裂解的Cas蛋白的构象变化。混合量子力学/分子力学(QM/MM)方法和ab-initio MD将用于阐明驱动核酸催化的化学机制的细节,具有提高催化效率和指导酶设计的潜力。计算研究将与实验学家合作协调,以协助解释实验数据并实现可测试的预测。总的来说,本研究将有助于阐明这些新兴CRISPR-Cas系统的生物分子功能,弥合理解分子机制和工程应用之间的差距。该奖项反映了美国国家科学基金会的法定使命,并通过使用基金会的知识价值和更广泛的影响审查标准进行评估,被认为值得支持。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Enhancement of CRISPR/Cas12a trans-cleavage activity using hairpin DNA reporters.
  • DOI:
    10.1093/nar/gkac578
  • 发表时间:
    2022-08-12
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Rossetti, Marianna;Merlo, Rosa;Bagheri, Neda;Moscone, Danila;Valenti, Anna;Saha, Aakash;Arantes, Pablo R.;Ippodrino, Rudy;Ricci, Francesco;Treglia, Ida;Delibato, Elisabetta;van der Oost, John;Palermo, Giulia;Perugino, Giuseppe;Porchetta, Alessandro
  • 通讯作者:
    Porchetta, Alessandro
Establishing the fundamental rules for genetic code expansion
建立遗传密码扩展的基本规则
  • DOI:
    10.1038/s41557-023-01243-9
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    21.8
  • 作者:
    Sinha, Souvik;Ahsan, Mohd;Palermo, Giulia
  • 通讯作者:
    Palermo, Giulia
The electronic structure of genome editors from the first principles
从第一原理看基因组编辑器的电子结构
  • DOI:
    10.1088/2516-1075/acb410
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    2.6
  • 作者:
    Nierzwicki, Łukasz;Ahsan, Mohd;Palermo, Giulia
  • 通讯作者:
    Palermo, Giulia
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Giulia Palermo其他文献

Computational Chemistry for Drug Discovery
药物发现的计算化学
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Giulia Palermo;M. Vivo
  • 通讯作者:
    M. Vivo
Theory and computation early career award talk: unraveling the CRISPR-Cas revolution through the lens of computational biophysics
  • DOI:
    10.1016/j.bpj.2022.11.251
  • 发表时间:
    2023-02-10
  • 期刊:
  • 影响因子:
  • 作者:
    Giulia Palermo
  • 通讯作者:
    Giulia Palermo
Folding and unfolding of an alpha-helical lid govern target double-stranded DNA break in Cas12a
  • DOI:
    10.1016/j.bpj.2023.11.432
  • 发表时间:
    2024-02-08
  • 期刊:
  • 影响因子:
  • 作者:
    Aakash Saha;Isabel Strohkendl;Mohd Ahsan;Catherine Moy;Alexander-Hoi Nguyen;Rick Russel;David W. Taylor;Giulia Palermo
  • 通讯作者:
    Giulia Palermo
Dynamics and thermostability of HNH nuclease in divergent Cas9 species
  • DOI:
    10.1016/j.bpj.2022.11.907
  • 发表时间:
    2023-02-10
  • 期刊:
  • 影响因子:
  • 作者:
    Chinmai Pindi;Souvik Sinha;Helen Belato;Carmelissa Norbrun;Jinping Luo;Alexandra M. D'Ordine;Gerwald Jogl;George Lisi;Giulia Palermo
  • 通讯作者:
    Giulia Palermo
Biophysical origin of adenine base editors’ improved editing efficiency
  • DOI:
    10.1016/j.bpj.2023.11.2067
  • 发表时间:
    2024-02-08
  • 期刊:
  • 影响因子:
  • 作者:
    Pablo R. Arantes;Souvik Sinha;Xiaoyu Chen;Aakash Saha;Amun C. Patel;Matthew Sample;Lukasz Nierzwicki;Audrone Lapinaite;Giulia Palermo
  • 通讯作者:
    Giulia Palermo

Giulia Palermo的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Giulia Palermo', 18)}}的其他基金

Conference: Chemistry Early Career Investigator Workshop
会议:化学早期职业研究员研讨会
  • 批准号:
    2417805
  • 财政年份:
    2024
  • 资助金额:
    $ 65.01万
  • 项目类别:
    Standard Grant
Mechanistic investigation of DNA cleavage and specificity in CRISPR-Cas9
CRISPR-Cas9 中 DNA 切割和特异性的机制研究
  • 批准号:
    1905374
  • 财政年份:
    2019
  • 资助金额:
    $ 65.01万
  • 项目类别:
    Continuing Grant

相似海外基金

CAS: Cu, Fe, and Ni Pincer Complexes: A Platform for Fundamental Mechanistic Investigations and Reaction Discovery
CAS:Cu、Fe 和 Ni 钳配合物:基础机理研究和反应发现的平台
  • 批准号:
    2349827
  • 财政年份:
    2024
  • 资助金额:
    $ 65.01万
  • 项目类别:
    Continuing Grant
Mechanistic Investigations in Homogeneous Catalysis
均相催化机理研究
  • 批准号:
    2892843
  • 财政年份:
    2023
  • 资助金额:
    $ 65.01万
  • 项目类别:
    Studentship
Mechanistic Investigations of Nickel-Promoted C-Heteroatom Bond Making Reactions
镍促进的 C-杂原子成键反应的机理研究
  • 批准号:
    RGPIN-2021-03959
  • 财政年份:
    2022
  • 资助金额:
    $ 65.01万
  • 项目类别:
    Discovery Grants Program - Individual
Iron-sulfur Clusters as Biological Sensors: Mechanistic Investigations by Synthetic Modeling Studies
铁硫簇作为生物传感器:通过综合建模研究进行机理研究
  • 批准号:
    2203879
  • 财政年份:
    2022
  • 资助金额:
    $ 65.01万
  • 项目类别:
    Standard Grant
Reparative macrophage transplantation as a next-generation cell-based therapy for myocardial infarction: towards clinical translation and mechanistic investigations
修复性巨噬细胞移植作为下一代基于细胞的心肌梗死疗法:临床转化和机制研究
  • 批准号:
    21K21351
  • 财政年份:
    2022
  • 资助金额:
    $ 65.01万
  • 项目类别:
    Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)
Mechanistic investigations of microbiome-driven aryl hydrocarbon receptor activity and macrophage function in pancreatic cancer.
胰腺癌中微生物驱动的芳烃受体活性和巨噬细胞功能的机制研究。
  • 批准号:
    10397510
  • 财政年份:
    2021
  • 资助金额:
    $ 65.01万
  • 项目类别:
Mechanistic investigations of microbiome-driven aryl hydrocarbon receptor activity and macrophage function in pancreatic cancer.
胰腺癌中微生物驱动的芳烃受体活性和巨噬细胞功能的机制研究。
  • 批准号:
    10611911
  • 财政年份:
    2021
  • 资助金额:
    $ 65.01万
  • 项目类别:
Mechanistic Investigations of Nickel-Promoted C-Heteroatom Bond Making Reactions
镍促进的 C-杂原子成键反应的机理研究
  • 批准号:
    RGPIN-2021-03959
  • 财政年份:
    2021
  • 资助金额:
    $ 65.01万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanistic investigations of HIV restriction by Serincs
Serincs 限制 HIV 的机制研究
  • 批准号:
    9927150
  • 财政年份:
    2020
  • 资助金额:
    $ 65.01万
  • 项目类别:
Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects
颗粒酶A介导的γ9δ2 T细胞结核病保护作用的机制研究
  • 批准号:
    10268163
  • 财政年份:
    2020
  • 资助金额:
    $ 65.01万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了