Re-Balancing Replica Exchange with Solute Tempering for Sampling Dynamic Protein Conformations
Re-Balancing Replica Exchange with Solute Tempering for Sampling Dynamic Protein Conformations
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DOI：
10.1021/acs.jctc.2c01139
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发表时间：
2023-03-14
影响因子：
5.5
通讯作者：
Chen，Jianhan
中科院分区：
文献类型：
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作者：
Zhang，Yumeng;Liu，Xiaorong;Chen，Jianhan
具有溶质回火的副本交换(REST)是在生物分子显式溶剂模拟中用于增强采样的副本交换的一种高效变体。通过对系统选定的“溶质”区域的哈密顿量进行缩放，REST有效地仅对感兴趣的自由度应用回火，而不对系统的其余部分(“溶剂”)进行回火，从而允许较少的复制品覆盖相同的温度范围。REST的一个关键考虑因素是如何将溶质-溶剂相互作用与溶质-溶质相互作用按比例放在一起。在这里，我们严格评估最新的REST2协议的性能，采样大规模的构象波动的内在无序蛋白质(IDPs)。结果表明，REST2在高有效温度下促进人工蛋白质构象崩塌，这似乎是为了促进小蛋白可逆折叠的采样而设计的功能。对于较大的国内流离失所者，崩溃尤其严重，导致有效温度空间中的复制品分离，并阻碍对大规模构象变化的有效采样。我们认为，溶质-溶剂相互作用的标度可以视为静止时的自由参数，可以通过调节这些参数来控制不同有效温度下的溶质构象性质(如链膨胀)，从而实现更有效的采样。为此，我们推导了一个新的REST3协议，其中重新校准了溶质-溶剂van der Waals相互作用的强度，以再现高有效温度下的蛋白质链扩展水平。使用两个具有非平凡的局部和远程结构特征的IDPs来检验REST3的效率，这些结构特征包括转录因子CREB的P53 N末端结构域和激酶诱导的反式激活结构域。结果表明，REST3导致了更有效的温度随机游走和改进的采样效率，这也进一步减少了所需的副本数量。尽管如此，我们的分析也揭示了仅依靠回火来采样无序蛋白质的大规模构象波动的重大挑战。很可能更有效的采样协议除了回火之外，还需要结合更复杂的哈密顿副本交换方案。
Replica exchange with solute tempering (REST) is a highly effective variant of replica exchange for enhanced sampling in explicit solvent simulations of biomolecules. By scaling the Hamiltonian for a selected “solute” region of the system, REST effectively applies tempering only to the degrees of freedom of interest but not the rest of the system (“solvent”), allowing fewer replicas for covering the same temperature range. A key consideration of REST is how the solute–solvent interactions are scaled together with the solute–solute interactions. Here, we critically evaluate the performance of the latest REST2 protocol for sampling large-scale conformation fluctuations of intrinsically disordered proteins (IDPs). The results show that REST2 promotes artificial protein conformational collapse at high effective temperatures, which seems to be a designed feature originally to promote the sampling of reversible folding of small proteins. The collapse is particularly severe with larger IDPs, leading to replica segregation in the effective temperature space and hindering effective sampling of large-scale conformational changes. We propose that the scaling of the solute–solvent interactions can be treated as free parameters in REST, which can be tuned to control the solute conformational properties (e.g., chain expansion) at different effective temperatures and achieve more effective sampling. To this end, we derive a new REST3 protocol, where the strengths of the solute–solvent van der Waals interactions are recalibrated to reproduce the levels of protein chain expansion at high effective temperatures. The efficiency of REST3 is examined using two IDPs with nontrivial local and long-range structural features, including the p53 N-terminal domain and the kinase inducible transactivation domain of transcription factor CREB. The results suggest that REST3 leads to a much more efficient temperature random walk and improved sampling efficiency, which also further reduces the number of replicas required. Nonetheless, our analysis also reveals significant challenges of relying on tempering alone for sampling large-scale conformational fluctuations of disordered proteins. It is likely that more efficient sampling protocols will require incorporating more sophisticated Hamiltonian replica exchange schemes in addition to tempering.