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

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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.