Production of Distinct Fibrillar, Oligomeric, and Other Aggregation States from Network Models of Multibody Interaction,Journal of Chemical Theory and Computation

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Production of Distinct Fibrillar, Oligomeric, and Other Aggregation States from Network Models of Multibody Interaction
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2024-09-11 , DOI: 10.1021/acs.jctc.4c00916
Elizabeth M Diessner ₁ , Loring J Thomas ₂ , Carter T Butts _{2,

3}

Affiliation

Protein aggregation can produce a wide range of states, ranging from fibrillar structures and oligomers to unstructured and semistructured gel phases. Recent work has shown that many of these states can be recapitulated by relatively simple, topological models specified in terms of multibody interaction energies, providing a direct connection between aggregate intermolecular forces and aggregation products. Here, we examine a low-dimensional network Hamiltonian model (NHM) based on four basic multibody interactions found in any aggregate system. We characterize the phase behavior of this NHM family, showing that fibrils arise from a balance between elongation-inducing and contact-inhibiting forces. Complex oligomers (including annular oligomers resembling those thought to be toxic species in Alzheimer’s disease) also form distinct phases in this regime, controlled in part by closure-inducing forces. We show that phase structure is largely independent of system size, and provide evidence of a rich structure of minor oligomeric phases that can arise from appropriate conditions. We characterize the phase behavior of this NHM family, demonstrating the range of ordered and disordered aggregation states possible with this set of interactions. As we show, fibrils arise from a balance between elongation-inducing and contact-inhibiting forces, existing in a regime bounded by gel-like and disaggregated phases; complex oligomers (including annular oligomers resembling those thought to be toxic species in Alzheimer’s disease) also form distinct phases in this regime, controlled in part by closure-inducing forces. We show that phase structure is largely independent of system size, allowing generalization to macroscopic systems, and provide evidence of a rich structure of minor oligomeric phases that can arise from appropriate conditions.

中文翻译：

从多体交互的网络模型中产生不同的纤维、寡聚和其他聚集状态

蛋白质聚集可以产生多种状态，从纤维结构和低聚物到非结构化和半结构化凝胶相。最近的工作表明，其中许多状态可以通过相对简单的多体相互作用能量指定的拓扑模型来概括，从而提供聚合分子间力和聚合产物之间的直接联系。在这里，我们研究了一个低维网络哈密顿模型（NHM），该模型基于任何聚合系统中发现的四种基本多体相互作用。我们描述了该 NHM 家族的相行为，表明原纤维是由伸长诱导力和接触抑制力之间的平衡产生的。复杂的低聚物（包括类似于阿尔茨海默病中有毒物质的环状低聚物）也在该状态中形成不同的相，部分由闭合诱导力控制。我们证明相结构在很大程度上与系统尺寸无关，并提供了适当条件下可以产生丰富的次要寡聚相结构的证据。我们描述了该 NHM 家族的相行为，展示了这组相互作用可能出现的有序和无序聚集状态的范围。正如我们所表明的，原纤维是由伸长诱导力和接触抑制力之间的平衡产生的，存在于由凝胶状和分解相界定的状态中；复杂的低聚物（包括类似于阿尔茨海默病中有毒物质的环状低聚物）也在该状态中形成不同的相，部分由闭合诱导力控制。我们证明相结构在很大程度上独立于系统尺寸，从而可以推广到宏观系统，并提供了适当条件下可以产生丰富的次要寡聚相结构的证据。

更新日期：2024-09-11

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