Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), 81377 Munich, Germany.
J Chem Theory Comput. 2024 Jul 9;20(13):5751-5762. doi: 10.1021/acs.jctc.4c00199. Epub 2024 May 8.
Water-mediated proton transfer reactions are central for catalytic processes in a wide range of biochemical systems, ranging from biological energy conversion to chemical transformations in the metabolism. Yet, the accurate computational treatment of such complex biochemical reactions is highly challenging and requires the application of multiscale methods, in particular hybrid quantum/classical (QM/MM) approaches combined with free energy simulations. Here, we combine the unique exploration power of new advanced sampling methods with density functional theory (DFT)-based QM/MM free energy methods for multiscale simulations of long-range protonation dynamics in biological systems. In this regard, we show that combining multiple walkers/well-tempered metadynamics with an extended system adaptive biasing force method (MWE) provides a powerful approach for exploration of water-mediated proton transfer reactions in complex biochemical systems. We compare and combine the MWE method also with QM/MM umbrella sampling and explore the sampling of the free energy landscape with both geometric (linear combination of proton transfer distances) and physical (center of excess charge) reaction coordinates and show how these affect the convergence of the potential of mean force (PMF) and the activation free energy. We find that the QM/MM-MWE method can efficiently explore both direct and water-mediated proton transfer pathways together with forward and reverse hole transfer mechanisms in the highly complex proton channel of respiratory Complex I, while the QM/MM-US approach shows a systematic convergence of selected long-range proton transfer pathways. In this regard, we show that the PMF along multiple proton transfer pathways is recovered by combining the strengths of both approaches in a QM/MM-MWE/focused US (FUS) scheme and reveals new mechanistic insight into the proton transfer principles of Complex I. Our findings provide a promising basis for the quantitative multiscale simulations of long-range proton transfer reactions in biological systems.
水介导的质子转移反应是广泛的生化系统中催化过程的核心，从生物能量转换到代谢中的化学转化。然而，准确计算处理这种复杂的生化反应极具挑战性，需要应用多尺度方法，特别是结合自由能模拟的混合量子/经典（QM/MM）方法。在这里，我们将新的先进采样方法的独特探索能力与基于密度泛函理论（DFT）的QM/MM 自由能方法相结合，用于生物系统中长程质子化动力学的多尺度模拟。在这方面，我们表明，将多个walker/well-tempered 元动力学与扩展系统自适应偏置力方法（MWE）相结合，为探索复杂生化系统中的水介导质子转移反应提供了一种强大的方法。我们比较并结合了 MWE 方法，也与 QM/MM 伞状采样相结合，并探索了自由能景观的采样，使用几何（质子转移距离的线性组合）和物理（过剩电荷中心）反应坐标，并展示了这些如何影响平均力势（PMF）和激活自由能的收敛。我们发现，QM/MM-MWE 方法可以有效地探索呼吸复合物 I 中高度复杂质子通道中的直接和水介导质子转移途径，以及正向和反向空穴转移机制，而 QM/MM-US 方法显示出选定长程质子转移途径的系统收敛性。在这方面，我们表明，通过在 QM/MM-MWE/focused US（FUS）方案中结合两种方法的优势，可以恢复沿多个质子转移途径的 PMF，并揭示了复合物 I 质子转移原理的新机制见解。我们的发现为生物系统中长程质子转移反应的定量多尺度模拟提供了有希望的基础。
