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CAREER: Molecular and Data-Centric Modeling of Cell-Penetrating Nanoparticles

职业：细胞穿透纳米颗粒的分子和以数据为中心的建模

基本信息

批准号：
2044997
负责人：
Reid Van Lehn
金额：
$ 58.12万
依托单位：
University of Wisconsin-Madison
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2044997&HistoricalAwards=false
关键词：
CAREER Molecular Data Centric Modeling

项目摘要

NONTECHNICAL SUMMARYThe Division of Materials Research in the Mathematical and Physical Sciences Directorate and the Division of Chemical, Bioengineering, Environmental and Transport Systems in the Engineering Directorate contribute funds to this CAREER award. It supports research, educational, and outreach activities to advance the fundamental understanding and design of nanomaterials. Spherical metal nanoparticles less than 10 nanometers in diameter are promising materials for biomedical applications because they can circulate in the bloodstream for long periods of time and interact with target cells. Some applications, such as the delivery of nucleic acids, require nanoparticles to enter the cell interior by crossing the cell membrane - the barrier that separates the cell interior from the environment - without damaging the cell. A small number of nanoparticles have exhibited this desirable cell entry behavior, but the mechanisms underlying this behavior are not understood. Consequently, general rules for designing nanoparticles that can efficiently cross the cell membrane do not exist.The PI will utilize a combination of computational methods to address this knowledge gap and test hypotheses to understand how the properties of nanoparticles affect their interaction with cell membranes. Such methods permit the analysis of nanoparticle properties and interactions that are difficult to discern experimentally and to gain insight into the fundamental mechanisms by which nanoparticles enter cells. New machine learning methods will be further developed to predict how nanoparticle properties can be synthetically tuned to facilitate cell entry. This computational approach will permit the creation of new types of nanoparticles more rapidly than would be possible through experiments alone, enabling the rational design of next-generation nanomaterials with various biomedical applications.This award also supports integrated education and outreach activities. The PI will create visually appealing, interactive, and easily accessible computer simulations that illustrate molecular-scale phenomena. These simulations will be used as a “computational microscope” to demonstrate nanoscale phenomena to the public and grade 6-12 students during events hosted on the University of Wisconsin-Madison campus. They will also be integrated into a range of undergraduate chemical engineering courses and disseminated broadly through online resources. The project will further help train the next generation of scientists in computational science by providing research opportunities for undergraduate students from underrepresented groups and local high school teachers. TECHNICAL SUMMARYThis CAREER award supports research, and integrated educational, and outreach activities to advance the fundamental understanding and design of functionalized nanomaterials. Designing materials to efficiently deliver cargo to intracellular targets without adverse side effects would have a transformative impact on biomedical applications including protein and drug delivery, gene editing, and bioimaging. Surface-functionalized gold nanoparticles have the potential to achieve this goal, but a longstanding challenge is designing nanoparticles that can enter cells without being trapped in endosomes and without disrupting the cell membrane. Surprisingly, some nanoparticles can non-disruptively penetrate into cells by translocating across the cell membrane, potentially enabling exciting new avenues for intracellular delivery. However, cell penetration mechanisms remain largely unknown, inhibiting the optimization and design of cell-penetrating nanoparticles.To address this knowledge gap, this project will use molecular dynamics simulations at multiple length scales to understand the thermodynamic and kinetic factors that influence the insertion of nanoparticles into lipid bilayers and test the hypothesis that bilayer insertion predicts cell penetration. The objectives of this project are to: (1) characterize mechanisms of bilayer insertion for different nanoparticle compositions using all-atom simulations with enhanced sampling techniques, (2) determine the impact of bilayer composition on nanoparticle insertion and penetration with coarse-grained simulations, and (3) train machine learning models to discover new classes of synthetically accessible cell-penetrating nanoparticles. Computational predictions of new cell-penetrating nanoparticles will be experimentally verified by collaborators at the University of Wisconsin-Madison. These studies will provide new insight into nano-bio interactions that will impact understanding of diverse classes of nanomaterials and demonstrate how the combination of machine learning and molecular simulation can inform nanomaterial design.This award also supports integrated education and outreach activities. The PI will design simulation modules that utilize molecular dynamics simulations to illustrate nanoscale phenomena. Modules will be: (1) visually appealing, to engage students and illustrate concepts; (2) interactive, to increase student engagement and improve learning outcomes; (3) accessible, to ensure simulations can be performed without computational expertise; and (4) distributable, to maximize impact without requiring substantial computational resources. Modules will be designed in collaboration with educational experts then integrated into outreach events to impact grade 6-12 students, integrated into classes within the University of Wisconsin-Madison chemical engineering curriculum to engage undergraduate students, and will be disseminated online to the broader nanomaterials education community. Module development will also broaden participation by providing opportunities for undergraduates from underrepresented groups to contribute to the project’s research activities.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.

数学和物理科学理事会的材料研究部和工程理事会的化学、生物工程、环境和运输系统部为该职业奖提供资金。它支持研究、教育和推广活动，以促进对纳米材料的基本理解和设计。直径小于10纳米的球形金属纳米颗粒是很有希望应用于生物医学的材料，因为它们可以在血液中循环很长一段时间，并与靶细胞相互作用。一些应用，例如核酸的递送，需要纳米颗粒穿过细胞膜进入细胞内部，而不损害细胞。细胞膜是将细胞内部与环境分开的屏障。少数纳米颗粒表现出这种理想的细胞进入行为，但这种行为背后的机制尚不清楚。因此，设计能有效穿过细胞膜的纳米粒子的一般规则并不存在。PI将利用计算方法的组合来解决这一知识缺口，并测试假设，以了解纳米颗粒的特性如何影响它们与细胞膜的相互作用。这样的方法可以分析纳米粒子的性质和相互作用，这在实验上是很难辨别的，并且可以深入了解纳米粒子进入细胞的基本机制。新的机器学习方法将进一步发展，以预测如何综合调整纳米颗粒的特性以促进细胞进入。这种计算方法将允许比单独通过实验更快地创造新型纳米颗粒，从而使具有各种生物医学应用的下一代纳米材料的合理设计成为可能。该奖项还支持综合教育和外展活动。PI将创建具有视觉吸引力、互动性和易于访问的计算机模拟，以说明分子尺度现象。这些模拟将被用作“计算显微镜”，在威斯康星大学麦迪逊分校举办的活动期间向公众和6-12年级的学生展示纳米级现象。它们还将被整合到一系列本科化学工程课程中，并通过在线资源广泛传播。该项目将为来自代表性不足群体的本科生和当地高中教师提供研究机会，进一步帮助培养计算科学领域的下一代科学家。本职业奖支持研究、综合教育和推广活动，以促进对功能化纳米材料的基本理解和设计。设计能够有效地将货物运送到细胞内目标而没有不良副作用的材料将对生物医学应用产生变革性影响，包括蛋白质和药物输送、基因编辑和生物成像。表面功能化的金纳米颗粒有可能实现这一目标，但长期存在的挑战是设计能够进入细胞而不被困在核内体中且不破坏细胞膜的纳米颗粒。令人惊讶的是，一些纳米颗粒可以通过跨细胞膜转运而非破坏性地渗透到细胞中，这可能为细胞内递送提供令人兴奋的新途径。然而，细胞穿透机制在很大程度上仍然未知，这阻碍了细胞穿透纳米颗粒的优化和设计。为了解决这一知识差距，该项目将在多个长度尺度上使用分子动力学模拟来了解影响纳米颗粒插入脂质双层的热力学和动力学因素，并测试双层插入预测细胞渗透的假设。该项目的目标是：(1)使用增强采样技术的全原子模拟来表征不同纳米颗粒组成的双层插入机制；(2)使用粗粒度模拟来确定双层组成对纳米颗粒插入和穿透的影响；(3)训练机器学习模型来发现新的合成可达细胞穿透纳米颗粒类别。新的细胞穿透纳米粒子的计算预测将由威斯康星大学麦迪逊分校的合作者进行实验验证。这些研究将为纳米生物相互作用提供新的见解，这将影响对不同类别纳米材料的理解，并展示机器学习和分子模拟的结合如何为纳米材料设计提供信息。该奖项还支持综合教育和外展活动。PI将设计模拟模块，利用分子动力学模拟来说明纳米级现象。模块将：(1)视觉上吸引人，吸引学生并说明概念；(2)互动性，提高学生参与度，改善学习成果；(3)可访问性，以确保在没有计算专业知识的情况下可以进行模拟；(4)可分配，在不需要大量计算资源的情况下最大化影响。模块将与教育专家合作设计，然后整合到外展活动中，影响6-12年级的学生，整合到威斯康星大学麦迪逊分校化学工程课程中，吸引本科生，并将在网上传播到更广泛的纳米材料教育社区。模块开发还将为来自代表性不足群体的本科生提供参与项目研究活动的机会，从而扩大参与范围。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）

Predicting the Physicochemical Properties and Biological Activities of Monolayer-Protected Gold Nanoparticles Using Simulation-Derived Descriptors

DOI：
10.1021/acsnano.2c00301
发表时间：
2022-04-26
期刊：
ACS NANO
影响因子：
17.1
作者：
Chew, Alex K.;Pedersen, Joel A.;Van Lehn, Reid C.
通讯作者：
Van Lehn, Reid C.

Topological Analysis of Molecular Dynamics Simulations using the Euler Characteristic

使用欧拉特性进行分子动力学模拟的拓扑分析

DOI：
10.1021/acs.jctc.2c00766
发表时间：
2023
期刊：
Journal of Chemical Theory and Computation
影响因子：
5.5
作者：
Smith, Alexander;Runde, Spencer;Chew, Alex K.;Kelkar, Atharva S.;Maheshwari, Utkarsh;Van Lehn, Reid C.;Zavala, Victor M.
通讯作者：
Zavala, Victor M.

Ligand Lipophilicity Determines Molecular Mechanisms of Nanoparticle Adsorption to Lipid Bilayers