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平衡状态下多组分生物分子系统的直接模型构建与分析。

Straightforward model construction and analysis of multicomponent biomolecular systems in equilibrium.

作者信息

Geertjens Nick H J, de Vink Pim J, Wezeman Tim, Markvoort Albert J, Brunsveld Luc

机构信息

Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2 Eindhoven 5612 AZ The Netherlands

Computational Biology Group, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513 Eindhoven 5600 MB The Netherlands

出版信息

RSC Chem Biol. 2023 Jan 18;4(4):252-260. doi: 10.1039/d2cb00211f. eCollection 2023 Apr 5.

Abstract

Mathematical modelling of molecular systems can be extremely helpful in elucidating complex phenomena in (bio)chemistry. However, equilibrium conditions in systems consisting of more than two components, such as for molecular glues bound to two proteins, can typically not be analytically determined without assumptions and (semi-)numerical models are not trivial to derive by the non-expert. Here we present a framework for equilibrium models, geared towards molecular glues and other contemporary multicomponent chemical biology challenges. The framework utilizes a general derivation method capable of generating custom mass-balance models for equilibrium conditions of complex molecular systems, based on the simple, reversible biomolecular reactions describing these systems. Several chemical biology concepts are revisited the framework to demonstrate the simplicity, generality and validity of the approach. The ease of use of the framework and the ability to both analyze systems and gain additional insights in the underlying parameters driving equilibria formation strongly aids the analysis and understanding of biomolecular systems. New directions for research and analysis are brought forward based on the model formation and system and parameter analysis. This conceptual framework severely reduces the time and expertise requirements which currently impede the broad integration of such valuable equilibrium models into molecular glue development and chemical biology research.

摘要

分子系统的数学建模对于阐明(生物)化学中的复杂现象可能极其有用。然而,由两个以上组分组成的系统中的平衡条件,例如与两种蛋白质结合的分子胶水的平衡条件,通常在没有假设的情况下无法通过解析确定,并且非专业人员推导(半)数值模型并非易事。在此,我们提出了一个针对分子胶水和其他当代多组分化学生物学挑战的平衡模型框架。该框架利用一种通用的推导方法,基于描述这些系统的简单、可逆生物分子反应,能够为复杂分子系统的平衡条件生成定制的质量平衡模型。通过该框架重新审视了几个化学生物学概念,以证明该方法的简单性、通用性和有效性。该框架的易用性以及分析系统和深入了解驱动平衡形成的潜在参数的能力,极大地有助于对生物分子系统的分析和理解。基于模型构建以及系统和参数分析,提出了新的研究和分析方向。这个概念框架大大降低了时间和专业知识要求,目前这些要求阻碍了将此类有价值的平衡模型广泛整合到分子胶水开发和化学生物学研究中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6a0/10074561/4446c8dbd303/d2cb00211f-f1.jpg

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