EnzymAgglo - Multiscale model-based investigation of functional enzyme and protein agglomerates for biotechnological applications.Part 2: From structure to function

该模型基于对多酶系统和蛋白质团聚的结构定义过程的理解，以及它们与功能的关系（例如，活动）近年来受到越来越多的关注。随着近年来新的多尺度建模方法和计算能力的提高（特别是GPU），对这种大分子现象的详细研究和预测变得触手可及。为了实现这一目标，我们在第一个项目阶段开发了一个普遍适用的多尺度模型框架，称为“分子离散单元法（MDEM）”。具体来说，它侧重于根据工艺条件对此类系统的结构发展。它适用于大分子尺度（ms和µm），并将在项目第一阶段的剩余时间内完成。MDEM框架允许生物和技术上有趣的结构现象的调查，由于其加速5至7个数量级的模拟时间和/或规模相比，传统的MD。同时，通过对属性的各向异性考虑，它保留了必要的细观细节。虽然在第一个项目阶段，该框架是使用多酶丙酮酸脱氢酶复合物（PDC）作为模型系统建立的，但它已收到其他SPP项目合作伙伴的非常积极的反馈，用于许多其他过程和现象（例如，在油-水界面处的蛋白质吸收）。初步合作已经启动，并计划予以加强。项目第二阶段的重点将是在结构决定功能方面扩大多部门数字环境管理办法;扩大规模和时间范围;与特别方案项目伙伴合作，将已制定的框架应用于新的进程。为了实现这些目标，MDEM框架将与人口平衡模型相结合（例如，用于实验验证和参数研究）。此外，蛋白质-蛋白质和蛋白质-界面相互作用将被细化和扩展到覆盖密度效应（分子拥挤;扩散限制），和多个合作伙伴的竞争性相互作用。通过将MDEM与计算流体力学/有限体积计算方法耦合，从结构到功能进行推导，包括空间分辨的酶促反应和代谢物扩散动力学。将进行进一步的抽象，以实现更高规模的模型（称为“MDEM-2”），并推向过程规模：稳定连接的单元（例如，PDC的催化核心）被抽象为一个粒子，并使用来自MDEM的数据进行参数化。催化活性多酶系统的实验反馈将在内部获得，而与SPP项目合作伙伴的广泛合作正在开发和进行中，允许在各种工艺参数上改进和验证MDEM（-2）方法。

The model based understanding of the structure defining processes of multi-enzymatic systems and protein agglomeration, as well as their relation to function (e.g., activity) has received increasing interest in recent years. With new multi-scaled modeling approaches and increased computational capabilities in recent years (especially GPUs), the detailed investigation and prediction of such macromolecular phenomena comes into reach. To achieve this, we developed a generally applicable multi-scale model framework, termed “Molecular discrete element method (MDEM)”, during the first project phase.Specifically, it focuses on the structural development of such systems depending on process conditions. It applies on the macro-molecular scale (ms and µm) and will be finalized in the remaining time of the first period of the project. The MDEM framework allows investigations of biologically and technically interesting structural phenomena due to its speedup of 5 to 7 orders of magnitude with respect to simulation time and/or scale in comparison to traditional MD. At the same time, it retains the necessary detail on the meso-scale through anisotropic consideration of properties. While, during the first project phase, the framework was established using the multi-enzymatic pyruvate dehydrogenase complex (PDC) as a model system, it has received very positive feedback from other SPP project partners for applications to numerous other processes and phenomena (e.g., protein absorption at the oil-water interface). Initial collaborations have been initiated and are planned to be intensified. The focus of the second project phase will lie on expansion of the MDEM approach with respect to the determination of function from structure; increased size and time scales; and application of developed framework to new processes in collaboration with SPP project partners. To achieve these goals, the MDEM framework will be coupled to population balance modeling (e.g., for experimental validation and parameter studies). Further, protein-protein and protein-interface interaction will be refined and extended to cover density effects (molecular crowding; diffusion limitation), and competetive interaction of multiple partners. Deduction from structure to function will be done by coupling MDEM to computational fluid dynamics / finite volume computation method, including spatially resolved enzymatic reaction and metabolite diffusion kinetics. A further abstraction will take place to enable higher-scale model (termed “MDEM-2”) and push towards the process scale: Stably connected units (e.g., the catalytic core of PDC) are abstracted as one particle and parameterized using the data from MDEM. Experimental feedback for catalytically active multi-enzymatic systems will be obtained in-house, while extensive collaborations with SPP project partners are developing and ongoing, allowing to refine and verify the MDEM(-2) approach on wide variety of process parameters.