Formalizing Coarse-Grained Representations of Anisotropic Interactions at Multimeric Protein Interfaces Using Virtual Sites
Formalizing Coarse-Grained Representations of Anisotropic Interactions at Multimeric Protein Interfaces Using Virtual Sites
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DOI：
10.1021/acs.jpcb.3c07023
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发表时间：
2024-02-05
影响因子：
3.3
通讯作者：
Pak，Alexander J.
中科院分区：
文献类型：
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作者：
Christians，Luc F.;Halingstad，Ethan V.;Pak，Alexander J.
组装成多聚体复合物的生物大分子的分子模拟仍然是一个挑战，由于计算无法访问的长度和时间尺度。低分辨率和隐式溶剂粗粒度建模方法使用传统的非键合相互作用（两两和球形各向同性）已经能够部分解决这个差距。然而，这些模型可能无法捕捉复杂的各向异性相互作用存在于大分子界面，除非高阶相互作用势被纳入在计算成本为代价。在这项工作中，我们介绍了一种替代和系统的方法来表示定向相互作用在蛋白质-蛋白质界面使用虚拟网站限制成对相互作用。我们表明，虚拟网站的相互作用参数可以在一个相对熵最小化的框架内，通过只使用粗粒度的网站之间的已知统计信息进行优化。我们比较我们的虚拟站点模型与传统的粗粒度模型，使用两个案例研究的多聚体蛋白质组装，并发现虚拟站点模型预测成对的相关性具有更高的保真度，更重要的是，组装行为是形态学上与实验一致。我们的研究强调了各向异性相互作用表示的重要性，并为未来研究中更准确但计算效率更高的大分子组装粗粒度模拟铺平了道路。
Molecular simulations of biomacromolecules that assemble into multimeric complexes remain a challenge due to computationally inaccessible length and time scales. Low-resolution and implicit-solvent coarse-grained modeling approaches using traditional nonbonded interactions (both pairwise and spherically isotropic) have been able to partially address this gap. However, these models may fail to capture the complex anisotropic interactions present at macromolecular interfaces unless higher-order interaction potentials are incorporated at the expense of the computational cost. In this work, we introduce an alternate and systematic approach to represent directional interactions at protein–protein interfaces by using virtual sites restricted to pairwise interactions. We show that virtual site interaction parameters can be optimized within a relative entropy minimization framework by using only information from known statistics between coarse-grained sites. We compare our virtual site models to traditional coarse-grained models using two case studies of multimeric protein assemblies and find that the virtual site models predict pairwise correlations with higher fidelity and, more importantly, assembly behavior that is morphologically consistent with experiments. Our study underscores the importance of anisotropic interaction representations and paves the way for more accurate yet computationally efficient coarse-grained simulations of macromolecular assembly in future research.