We are pleased to dedicate this special issue of the Journal of Computational Chemistry, entitled “Membrane Protein Simulations and Free Energy Approaches”, to Professor Benoît Roux to mark the occasion of his 60th birthday. This issue is a collection of peer-reviewed articles contributed by 20 participants of a three-day symposium held for his 60th birthday celebration in August 2018 at the ACS 256th National Meeting in Boston, MA (Figure 1). This symposium was organized by three former Roux lab members (Wonpil Im, Nilesh Banavali, and Yun Lyna Luo) and brought together 46 of Benoît's friends, colleagues, and alumni. Benoît's seminal impact on the field of computational biophysics includes major innovations in quantitative free energy approaches to study molecular systems, which enabled deep advances in the understanding of membrane and protein dynamics and function. These inventive techniques have been also been applied to other challenging biological areas, such as macromolecular machines and protein-ligand binding. The articles selected in this special issue honor his pioneering research by showcasing the latest advances in biomolecular simulation, which demonstrate the vitality and variety of a computational biophysics community that Benoît has been instrumental in creating and fostering. Benoît and co-workers have been strongly involved in the development of two popular biomolecular modeling and molecular dynamics (MD) simulation software packages: CHARMM, dating back to his doctoral research with Professor Martin Karplus, and NAMD, through more recent collaborations with Professor Klaus Schulten. Novel method development has always been at the heart of Benoît's research program, and this is reflected in the research directions that his alumni have taken. In this issue, the Toby Allen group reviews the recent application of an atomistic string method, based on Benoît's “swarms-of-trajectories” approach, to elucidate the interdependence of conformational changes during pentameric ligand-gated ion channel activation. The Wonpil Im group presents a new tool in CHARMM-GUI that consists of two modules, Spin-Pair Distributor and restrained-ensemble MD Prepper, to setup simulations that utilize information from the powerful double electron–electron resonance (DEER) experiments. The Jose Faraldo-Gomez group presents a method to calculate the free energy of a shape transformation in a lipid membrane directly from enhanced sampling MD simulation using grid-based collective variable. The Yun Luo group reports a currentflow betweenness method for robust protein dynamical network analysis and revealed common changes in protein–protein networks among gain-of-function kinase mutants. Binding free energy calculations are an important objective in computational chemistry and drug design. Benoît is a trailblazer in absolute binding free energy calculations using both the alchemical double decoupling method and potential of mean force method. The David Minh group examines the impact of harmonic restraints on protein heavy atoms and ligand atoms on end-point free energy calculations. The Haibo Yu group uses implicit ligand sampling simulations to identify potential O2 binding site and migration pathways within a photoprotein obelin, which provides the basis for future computational studies of the bioluminescent mechanism. The Christopher Rowley group assesses several semi-empirical and density-functional theory (DFT) methods for their ability to describe the potential energy surface and reaction energies of the covalent modification of a thiol by an electrophile. The first polarizable model of water based on the classical Drude oscillator approach was developed by Guillaume Lamoureux, Alexander MacKerell Jr., and Benoît in 2003. Thanks to the continued efforts of Benoît and Alex, the Drude force field is now becoming the method of choice to account for induced polarization in large-scale biomolecular simulations. Two independent studies aimed at improving ion–π interactions are reported in this issue. The Guillaume Lamoureux group calibrates the Drude force field for complexes of alkali metal ions and ammoniums with aromatic model compounds. The Alexander MacKerell Jr. group systematically optimizes the parameters for anion-π interactions in proteins in the Drude-2013 protein polarizable force field. Lipid membranes serves as a physical barrier, substrate, and a mechanistically responsive environment in a wide range of physiological and pathological processes. The Christopher Chipot group calculates the free-energy and fractional-diffusivity profiles underlying membrane translocation and reveals that CO2 expands and loosens the membrane, which facilitates the permeation of the drug-like molecules. The Harel Weinstein group compares the responses of the membrane to the TMEM16 scramblases in flat membranes and nanodiscs. Using highly mobile membrane model and full membrane simulations, the Emad Tajkhorshid group reports the first observation of two distinct PIP3 binding modes on GRP1-PHD, demonstrate that concurrent binding of multiple anionic lipids by GRP1-PHD contributes to its membrane affinity. To understand the mechanism of cholesterol modification of hedgehog ligand, Nilesh Banavali models a cholesterol-bound drosophila Hh precursor and predicts atomic-detail pathways for the full autocatalytic reaction. The Yinglong Miao group DOI: 10.1002/jcc.26140

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庆祝 Benoît Roux 60 岁生日：量化膜上的生物学

我们很高兴将这期名为“膜蛋白模拟和自由能方法”的计算化学杂志特刊献给 Benoît Roux 教授，以纪念他 60 岁生日。本期收录了 20 位参加者在 2018 年 8 月在马萨诸塞州波士顿举行的 ACS 第 256 届全国会议上为庆祝他 60 岁生日而举办的为期三天的研讨会的同行评审文章（图 1）。本次研讨会由三位前 Roux 实验室成员（Wonpil Im、Nilesh Banavali 和 Yun Lyna Luo）组织，汇集了 Benoît 的 46 位朋友、同事和校友。Benoît 对计算生物物理学领域的开创性影响包括在研究分子系统的定量自由能方法方面的重大创新，这使得对膜和蛋白质动力学和功能的理解取得了深入进展。这些创造性技术也已应用于其他具有挑战性的生物领域，例如大分子机器和蛋白质-配体结合。本期特刊中选择的文章通过展示生物分子模拟的最新进展来表彰他的开创性研究，这些进展展示了 Benoît 一直在帮助创建和培育的计算生物物理学社区的活力和多样性。Benoît 及其同事积极参与了两种流行的生物分子建模和分子动力学 (MD) 模拟软件包的开发：CHARMM（可追溯到他与 Martin Karplus 教授的博士研究）和 NAMD（通过最近与 Klaus 教授的合作）舒尔滕。新方法开发一直是 Benoît 研究计划的核心，这反映在他的校友所采取的研究方向上。在本期中，Toby Allen 小组回顾了最近基于 Benoît 的“轨迹群”方法的原子弦方法的应用，以阐明五聚体配体门控离子通道激活过程中构象变化的相互依赖性。Wonpil Im 小组在 CHARMM-GUI 中展示了一个新工具，该工具由两个模块组成，即自旋对分配器和约束合奏 MD Prepper，以设置利用来自强大双电子 - 电子共振 (DEER) 实验的信息的模拟。Jose Faraldo-Gomez 小组提出了一种使用基于网格的集体变量的增强采样 MD 模拟直接计算脂质膜中形状变换自由能的方法。Yun Luo 小组报告了一种用于稳健蛋白质动力学网络分析的电流中介方法，并揭示了功能获得性激酶突变体之间蛋白质 - 蛋白质网络的常见变化。结合自由能计算是计算化学和药物设计中的一个重要目标。Benoît 是使用炼金术双解耦法和平均力势法计算绝对结合自由能的先驱。David Minh 小组研究了谐波约束对蛋白质重原子和配体原子对终点自由能计算的影响。Haibo Yu 小组使用隐式配体采样模拟来识别光蛋白 obelin 中潜在的 O2 结合位点和迁移途径，这为未来生物发光机制的计算研究提供了基础。Christopher Rowley 小组评估了几种半经验和密度泛函理论 (DFT) 方法，以评估它们描述亲电子试剂共价修饰硫醇的势能表面和反应能的能力。第一个基于经典德鲁德振荡器方法的可极化水模型由 Guillaume Lamoureux、Alexander MacKerell Jr. 和 Benoît 于 2003 年开发。由于 Benoît 和 Alex 的持续努力，德鲁德力场现在成为首选方法解释大规模生物分子模拟中的诱导极化。本期报道了两项旨在改善离子-π 相互作用的独立研究。Guillaume Lamoureux 小组校准了碱金属离子和铵与芳香模型化合物的配合物的德鲁德力场。Alexander MacKerell Jr. 小组系统地优化了 Drude-2013 蛋白质极化力场中蛋白质中阴离子-π 相互作用的参数。脂质膜在广泛的生理和病理过程中充当物理屏障、底物和机械响应环境。Christopher Chipot 小组计算了膜易位背后的自由能和分数扩散率曲线，并揭示了 CO2 使膜膨胀和松弛，从而促进了类药物分子的渗透。Harel Weinstein 小组比较了膜对平膜和纳米圆盘中 TMEM16 乱序的反应。Emad Tajkhorshid 小组使用高度流动的膜模型和全膜模拟，首次观察到 GRP1-PHD 上两种不同的 PIP3 结合模式，证明 GRP1-PHD 对多种阴离子脂质的同时结合有助于其膜亲和力。为了了解刺猬配体胆固醇修饰的机制，Nilesh Banavali 模拟了胆固醇结合的果蝇 Hh 前体，并预测了完全自催化反应的原子细节途径。应龙苗族DOI：10.1002/jcc.26140 Emad Tajkhorshid 小组报告了对 GRP1-PHD 上两种不同 PIP3 结合模式的首次观察，证明 GRP1-PHD 对多种阴离子脂质的同时结合有助于其膜亲和力。为了了解刺猬配体胆固醇修饰的机制，Nilesh Banavali 模拟了与胆固醇结合的果蝇 Hh 前体，并预测了完全自催化反应的原子细节途径。应龙苗族DOI：10.1002/jcc.26140 Emad Tajkhorshid 小组报告了对 GRP1-PHD 上两种不同 PIP3 结合模式的首次观察，证明 GRP1-PHD 对多种阴离子脂质的同时结合有助于其膜亲和力。为了了解刺猬配体胆固醇修饰的机制，Nilesh Banavali 模拟了与胆固醇结合的果蝇 Hh 前体，并预测了完全自催化反应的原子细节途径。应龙苗族DOI：10.1002/jcc.26140