Advanced Electrostatic Computation in Molecular Dynamics

分子动力学中的高级静电计算

• 批准号: 8042691
• 负责人: ALEXANDER H BOSCHITSCH
• 金额: $ 35.73万
• 依托单位: CONTINUUM DYNAMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8042691
• 关键词: Address; Adopted; Adoption; Adverse effects; Affinity; Behavior; Benchmarking; Binding; Binding Sites; Bioinformatics; Biological; Biological Process; Biophysics; Charge; Code; Communities; Complex; Computer software; Coupled; Coupling; Dependence; Designer Drugs; Development; Disease Progression; Docking; Drug Design; Drug Formulations; Drug Industry; Drug Packaging; Electrostatics; Ensure; Environment; Equation; Evaluation; Exercise; Free Energy; Generations; Goals; Imagery; Investigation; Ions; Ligands; Location; Mediating; Medical; Methods; Metric; Modeling; Molecular; Molecular Conformation; Molecular Models; Morphologic artifacts; Nucleic Acids; Nucleosomes; Output; Peptides; Pharmaceutical Preparations; Phase; Play; Potential Energy; Preclinical Drug Evaluation; Probability; Process; Property; Proteins; Research; Research Personnel; Resolution; Ribosomes; Role; Shapes; Side; Simulate; Site; Sodium Chloride; Software Tools; Solutions; Solvents; Specificity; Speed; Structure; Surface; System; Techniques; Time; Validation; base; commercialization; cost; design; direct application; drug candidate; drug development; drug efficacy; drug modification; flexibility; improved; innovation; insight; interest; meetings; molecular dynamics; molecular modeling; novel; open source; public health relevance; simulation; solute; success; tool

DESCRIPTION (provided by applicant): Advances in computational hardware and molecular modeling techniques have revolutionized our ability to simulate electrostatic interactions, which play a fundamental role in the conformational stability, structure, folding and function of biomolecules. One important near-term application of these developments drawing both theoretical and commercial interests is drug design where successful docking requires both shape and electrostatic complementarity. Currently, the continuum electrostatic description based upon the Poisson- Boltzmann Equation (PBE) offers the best combination of modeling fidelity and computational cost, however, numerical issues associated with nonlinear behavior in highly charged systems and solution convergence at the dielectric interface, have impaired accuracy and calculation time. As a result, adoption of PBE-based solvers in energy minimization, Monte Carlo and molecular dynamics codes has been limited. In Phase I, the numerical stability of the electrostatic solution, particularly the gradient contributions from the surface, were successfully addressed using a boundary-conforming mesh so that reliably convergent and accurate force predictions are achieved. The challenge of reliable convergence for highly charged systems was also resolved. These advances were implemented on an adaptive Cartesian mesh structure that offers unique intrinsic advantages over competing grid arrangements (i.e. lattices and unstructured tetrahedral grids) with regard to multigrid implementation, mesh generation and solution adaptation. The Phase II effort builds upon these successes by providing additional capabilities focused on drug design and packaged to facilitate transition and distribution of the software tools to end-users in the medical and pharmaceutical industries. The main technical developments envisioned to support this goal are: (i) Methods will be formulated and implemented to calculate the electrostatic interaction or binding potential and energy with greater accuracy and/or speed, thus promoting higher reliability and throughput in drug screening and design efforts. (ii) Short- range forces will be incorporated to model molecular flexibility thus providing a more complete description of the molecular dynamics for drug design application and understanding of biologicial function. (iii) New methods for evaluating metrics to assess docking probability and reject decoys will be developed along with an efficient formulation for estimating the gradients/sensitivities of these metrics. In the context of drug design these gradients would indicate changes to the drug geometry and charge distribution favorable for selective binding. Our biomolecular applications will build upon strengths of our current state-of-the-art PBE solver in providing accurate and fast predictions of electrostatic solvation free energies, binding free energies, surface electrostatic potential and derived quantitative metrics for highly charged and large-scale systems such as nucleic acids and its assemblies such as nucleosome and ribosome. PUBLIC HEALTH RELEVANCE: The research effort will develop and provide software tools and analysis and visualization techniques that: (i) are tailored towards improved protein and drug design and (ii) can be used to relate biological function of solvated biomolecules to its geometric, structural and electrostatic properties. For drug applications, the analysis will provide designers with the information needed to enhance drug affinity and specificity, ensuring it binds to target sites and rejects decoy locations, thus, ultimately, lowering drug development costs and times, and improving drug efficacy with reduced side-effects. Improved insights into the relationship between the physiochemical and geometric properties of biomolecules and their environment to biological function are useful for enhancing bioinformatics tools and achieving a better foundational understanding of the progression of diseases at the molecular level and the means to counter them.

描述（由申请人提供）：计算硬件和分子建模技术的进展彻底改变了我们模拟静电相互作用的能力，静电相互作用的能力在构象稳定性，结构，结构，折叠和功能中起着基本作用。这些发展的一项重要的近期应用既绘制理论和商业利益，又是药物设计，成功的对接需要形状和静电互补性。目前，基于Poisson-Boltzmann方程（PBE）的连续静电描述提供了建模忠诚度和计算成本的最佳组合，但是，与高电荷系统中非线性行为相关的数值问题以及在介质界面处的溶液收敛性的准确性和计算时间受损。结果，基于PBE的求解器在能量最小化，蒙特卡洛和分子动力学代码方面受到限制。 在第一阶段，使用构造边界的网格成功解决了静电溶液的数值稳定性，尤其是表面的梯度贡献，以便实现可靠的收敛性和准确的力预测。还解决了高电荷系统可靠收敛的挑战。这些进步是在自适应的笛卡尔网状结构上实施的，该结构在多族实施，网格生成和解决方案适应性方面，在竞争网格安排（即晶格和非结构化的四面体网格）方面提供了独特的内在优势。第二阶段的努力是基于这些成功的基础，它提供了针对药物设计的其他功能，并包装以促进软件工具的过渡和分发，以向医疗和制药行业的最终用户进行过渡和分发。旨在支持此目标的主要技术发展是：（i）将以更高的准确性和/或速度来制定和实施方法来计算静电相互作用或结合潜力和能量，从而促进药物筛查和设计工作中的更高可靠性和吞吐量。 （ii）短范围力将纳入模型分子柔韧性，从而为药物设计应用和对生物学功能的理解提供了更完整的描述。 （iii）将开发评估标准评估对接概率和拒绝诱饵的新方法，以及有效的制定方法，用于估计这些指标的梯度/敏感性。在药物设计的背景下，这些梯度将表明对药物几何形状的变化和有利于选择性结合的电荷分布。我们的生物分子应用将基于我们当前最先进的PBE求解器的优势，以提供对静电溶剂化的自由能的准确预测，结合自由能，表面静电电位和衍生的定量指标，用于高电荷和大规模的系统，例如核酸及其核酸和核素和核糖核体和核素。 公共卫生相关性：研究工作将开发并提供软件工具以及分析和可视化技术：（i）针对改进的蛋白质和药物设计量身定制，并且（ii）可用于将溶剂化的生物分子的生物学功能与其几何，结构和静电性特性相关联。对于药物应用，该分析将为设计师提供增强药物亲和力和特异性所需的信息，确保其与目标部位结合并拒绝诱饵位置，因此最终降低了药物开发成本和时间，并通过副作用降低来提高药物效率。对生物分子的生理化学和几何特性及其对生物功能的环境之间的关系的洞察力有助于增强生物信息学工具，并更好地了解分子水平疾病的进展以及对其进行反应的基础。

项目成果

Theoretical assessment of the oligolysine model for ionic interactions in protein-DNA complexes.

• DOI: 10.1021/jp204915y
• 发表时间: 2011-08-18
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Fenley, Marcia O.;Russo, Cristina;Manning, Gerald S.
• 通讯作者: Manning, Gerald S.

Influence of Grid Spacing in Poisson-Boltzmann Equation Binding Energy Estimation.

• DOI: 10.1021/ct300765w
• 发表时间: 2013-08-13
• 期刊: JOURNAL OF CHEMICAL THEORY AND COMPUTATION
• 影响因子: 5.5
• 作者: Harris, Robert C.;Boschitsch, Alexander H.;Fenley, Marcia O.
• 通讯作者: Fenley, Marcia O.

Excluded volume and ion-ion correlation effects on the ionic atmosphere around B-DNA: theory, simulations, and experiments.

• DOI: 10.1063/1.4902407
• 发表时间: 2014-12
• 期刊: The Journal of chemical physics
• 作者: Zaven Ovanesyan;Bharat K. Medasani;M. O. Fenley;G. I. Guerrero-García;M. O. de la Cruz;M. Marucho