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Faster but Not Sweeter: A Model of Escherichia coli Re-level Lipopolysaccharide for Martini 3 and a Martini 2 Version with Accelerated Kinetics 更快但不更甜:大肠杆菌再水平脂多糖的马尔蒂尼 3 模型和具有加速动力学的马尔蒂尼 2 版本
IF 5.5 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-15 DOI: 10.1021/acs.jctc.4c00374
Astrid F. Brandner, Dheeraj Prakaash, Alexandre Blanco González, Fergus Waterhouse, Syma Khalid
Lipopolysaccharide (LPS) is a complex glycolipid molecule that is the main lipidic component of the outer leaflet of the outer membrane of Gram-negative bacteria. It has very limited lateral motion compared to phospholipids, which are more ubiquitous in biological membranes, including in the inner leaflet of the outer membrane of Gram-negative bacteria. The slow-moving nature of LPS can present a hurdle for molecular dynamics simulations, given that the (pragmatically) accessible timescales to simulations are currently limited to microseconds, during which LPS displays some conformational dynamics but hardly any lateral diffusion. Thus, it is not feasible to observe phenomena such as insertion of molecules, including antibiotics/antimicrobials, directly into the outer membrane from the extracellular side nor to observe LPS dissociating from proteins via molecular dynamics using currently available models at the atomistic and more coarse-grained levels of granularity. Here, we present a model of deep rough LPS compatible with the Martini 2 coarse-grained force field with scaled down nonbonded interactions to enable faster diffusion. We show that the faster-diffusing LPS model is able to reproduce the salient biophysical properties of the standard models, but due to its faster lateral motion, molecules are able to penetrate deeper into membranes containing the faster model. We show that the fast ReLPS model is able to reproduce experimentally determined patterns of interaction with outer membrane proteins while also allowing for LPS to associate and dissociate with proteins within microsecond timescales. We also complete the Martini 3 LPS toolkit for Escherichia coli by presenting a (standard) model of deep rough LPS for this force field.
脂多糖(LPS)是一种复杂的糖脂分子,是革兰氏阴性细菌外膜外叶的主要脂质成分。与磷脂相比,它的横向运动非常有限,而磷脂在生物膜(包括革兰氏阴性细菌外膜的内叶)中更为普遍。LPS 的缓慢运动特性可能会给分子动力学模拟带来障碍,因为(从实用角度看)目前可用于模拟的时间尺度仅限于微秒级,在此期间,LPS 显示出一些构象动态,但几乎没有横向扩散。因此,使用目前可用的原子级和更粗粒度的模型,既无法观察到分子(包括抗生素/抗菌素)从细胞外侧直接插入外膜的现象,也无法通过分子动力学观察到 LPS 从蛋白质中解离的现象。在这里,我们提出了一个与马蒂尼 2 粗粒度力场兼容的深粗糙度 LPS 模型,该模型具有按比例缩小的非键相互作用,从而实现了更快的扩散。我们的研究表明,扩散速度更快的 LPS 模型能够再现标准模型的显著生物物理特性,但由于其横向运动速度更快,分子能够更深地穿透包含更快模型的膜。我们的研究表明,快速 ReLPS 模型能够再现实验所确定的与外膜蛋白相互作用的模式,同时还允许 LPS 在微秒级的时间尺度内与蛋白质结合和解离。我们还为大肠杆菌提供了一个适用于该力场的深度粗糙 LPS(标准)模型,从而完善了 Martini 3 LPS 工具包。
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引用次数: 0
Replica Exchange of Expanded Ensembles: A Generalized Ensemble Approach with Enhanced Flexibility and Parallelizability. 扩展集合的复制交换:增强灵活性和并行性的广义集合方法
IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-15 DOI: 10.1021/acs.jctc.4c00484
Wei-Tse Hsu, Michael R Shirts

Generalized ensemble methods such as Hamiltonian replica exchange (HREX) and expanded ensemble (EE) have been shown effective in free energy calculations for various contexts, given their ability to circumvent free energy barriers via nonphysical pathways defined by states with different modified Hamiltonians. However, both HREX and EE methods come with drawbacks, such as limited flexibility in parameter specification or the lack of parallelizability for more complicated applications. To address this challenge, we present the method of replica exchange of expanded ensembles (REXEE), which integrates the principles of HREX and EE methods by periodically exchanging coordinates of EE replicas sampling different yet overlapping sets of alchemical states. With the solvation free energy calculation of anthracene and binding free energy calculation of the CB7-10 binding complex, we show that the REXEE method achieves the same level of accuracy in free energy calculations as the HREX and EE methods, while offering enhanced flexibility and parallelizability. Additionally, we examined REXEE simulations with various setups to understand how different exchange frequencies and replica configurations influence the sampling efficiency in the fixed-weight phase and the weight convergence in the weight-updating phase. The REXEE approach can be further extended to support asynchronous parallelization schemes, allowing looser communications between larger numbers of loosely coupled processors such as cloud computing and therefore promising much more scalable and adaptive executions of alchemical free energy calculations. All algorithms for the REXEE method are available in the Python package ensemble_md, which offers an interface for REXEE simulation management without modifying the source code in GROMACS.

汉密尔顿复制交换(HREX)和扩展集合(EE)等广义集合方法能够通过由具有不同修正汉密尔顿的状态定义的非物理途径绕过自由能障碍,因此在各种情况下的自由能计算中被证明是有效的。然而,EREX 和 EE 方法都存在一些缺点,例如参数指定的灵活性有限,或者在更复杂的应用中缺乏并行性。为了应对这一挑战,我们提出了扩展集合的复制交换(REXEE)方法,该方法通过定期交换采样不同但重叠的炼金状态集的 EE 复制坐标,整合了EREX 和 EE 方法的原理。通过蒽的溶解自由能计算和 CB7-10 结合复合物的结合自由能计算,我们表明 REXEE 方法在自由能计算方面达到了与 HREX 和 EE 方法相同的精度水平,同时具有更高的灵活性和并行性。此外,我们研究了各种设置下的 REXEE 模拟,以了解不同的交换频率和复制配置如何影响固定权重阶段的采样效率和权重更新阶段的权重收敛性。REXEE 方法可以进一步扩展,以支持异步并行化方案,允许更多松散耦合的处理器(如云计算)之间进行更松散的通信,因此有望为炼金术自由能计算提供更具可扩展性和适应性的执行。REXEE方法的所有算法都可以在Python软件包ensemble_md中找到,它为REXEE模拟管理提供了一个接口,无需修改GROMACS中的源代码。
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引用次数: 0
Strategies to Obtain Reliable Energy Landscapes from Embedded Multireference Correlated Wavefunction Methods for Surface Reactions. 从表面反应的嵌入式多参考相关波函数方法中获取可靠能量景观的策略。
IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-14 DOI: 10.1021/acs.jctc.4c00558
Xuelan Wen, Jan-Niklas Boyn, John Mark P Martirez, Qing Zhao, Emily A Carter

Embedded correlated wavefunction (ECW) theory is a powerful tool for studying ground- and excited-state reaction mechanisms and associated energetics in heterogeneous catalysis. Several factors are important to obtaining reliable ECW energies, critically the construction of consistent active spaces (ASs) along reaction pathways when using a multireference correlated wavefunction (CW) method that relies on a subset of orbital spaces in the configuration interaction expansion to account for static electron correlation, e.g., complete AS self-consistent field theory, in addition to the adequate partitioning of the system into a cluster and environment, as well as the choice of a suitable basis set and number of states included in excited-state simulations. Here, we conducted a series of systematic studies to develop best-practice guidelines for ground- and excited-state ECW theory simulations, utilizing the decomposition of NH3 on Pd(111) as an example. We determine that ECW theory results are relatively insensitive to cluster size, the aug-cc-pVDZ basis set provides an adequate compromise between computational complexity and accuracy, and that a fixed-clean-surface approximation holds well for the derivation of the embedding potential. Additionally, we demonstrate that a merging approach, which involves generating ASs from the molecular fragments at each configuration, is preferable to a creeping approach, which utilizes ASs from adjacent structures as an initial guess, for the generation of consistent potential energy curves involving open-d-shell metal surfaces, and, finally, we show that it is essential to include bands of excited states in their entirety when simulating excited-state reaction pathways.

嵌入式相关波函数(ECW)理论是研究异相催化中基态和激发态反应机理及相关能量的有力工具。有几个因素对获得可靠的 ECW 能量非常重要,关键是在使用多参考相关波函数(CW)方法(该方法依赖于构型相互作用扩展中的轨道空间子集以考虑静态电子相关性)(例如完整的 AS 自洽场理论)时,沿反应路径构建一致的活性空间(AS),此外还需要将系统充分划分为簇和环境,以及选择合适的基集和激发态模拟中包含的状态数。在此,我们以 Pd(111) 上 NH3 的分解为例,进行了一系列系统研究,以制定基态和激发态 ECW 理论模拟的最佳实践指南。我们确定,ECW 理论结果对簇大小相对不敏感,aug-cc-pVDZ 基集在计算复杂性和准确性之间提供了适当的折衷,而且固定清洁表面近似对嵌入势的推导非常有效。此外,我们还证明了在生成涉及开 D 壳金属表面的一致势能曲线时,合并方法(包括从每个构型的分子片段生成 AS)优于爬行方法(利用相邻结构的 AS 作为初始猜测)。
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引用次数: 0
Accurate Quantum Monte Carlo Forces for Machine-Learned Force Fields: Ethanol as a Benchmark. 机器学习力场的精确量子蒙特卡洛力:以乙醇为基准。
IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-14 DOI: 10.1021/acs.jctc.4c00498
E Slootman, I Poltavsky, R Shinde, J Cocomello, S Moroni, A Tkatchenko, C Filippi

Quantum Monte Carlo (QMC) is a powerful method to calculate accurate energies and forces for molecular systems. In this work, we demonstrate how we can obtain accurate QMC forces for the fluxional ethanol molecule at room temperature by using either multideterminant Jastrow-Slater wave functions in variational Monte Carlo or just a single determinant in diffusion Monte Carlo. The excellent performance of our protocols is assessed against high-level coupled cluster calculations on a diverse set of representative configurations of the system. Finally, we train machine-learning force fields on the QMC forces and compare them to models trained on coupled cluster reference data, showing that a force field based on the diffusion Monte Carlo forces with a single determinant can faithfully reproduce coupled cluster power spectra in molecular dynamics simulations.

量子蒙特卡罗(QMC)是一种计算分子系统精确能量和力的强大方法。在这项研究中,我们展示了如何通过在变异蒙特卡洛中使用多行列式 Jastrow-Slater 波函数或在扩散蒙特卡洛中仅使用单行列式,获得室温下通量乙醇分子的精确 QMC 力。通过对该系统的各种代表性构型进行高水平耦合聚类计算,评估了我们协议的卓越性能。最后,我们在 QMC 力上训练了机器学习力场,并将其与在耦合簇参考数据上训练的模型进行了比较,结果表明,基于扩散蒙特卡罗力和单一行列式的力场可以在分子动力学模拟中忠实地再现耦合簇功率谱。
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引用次数: 0
Ligand Gaussian Accelerated Molecular Dynamics 3 (LiGaMD3): Improved Calculations of Binding Thermodynamics and Kinetics of Both Small Molecules and Flexible Peptides 配体高斯加速分子动力学 3 (LiGaMD3):改进小分子和柔性多肽的结合热力学和动力学计算
IF 5.5 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-13 DOI: 10.1021/acs.jctc.4c00502
Jinan Wang, Yinglong Miao
Binding thermodynamics and kinetics play critical roles in drug design. However, it has proven challenging to efficiently predict ligand binding thermodynamics and kinetics of small molecules and flexible peptides using conventional molecular dynamics (cMD), due to limited simulation time scales. Based on our previously developed ligand Gaussian accelerated molecular dynamics (LiGaMD) method, we present a new approach, termed “LiGaMD3″, in which we introduce triple boosts into three individual energy terms that play important roles in small-molecule/peptide dissociation, rebinding, and system conformational changes to improve the sampling efficiency of small-molecule/peptide interactions with target proteins. To validate the performance of LiGaMD3, MDM2 bound by a small molecule (Nutlin 3) and two highly flexible peptides (PMI and P53) were chosen as the model systems. LiGaMD3 could efficiently capture repetitive small-molecule/peptide dissociation and binding events within 2 μs simulations. The predicted binding kinetic constant rates and free energies from LiGaMD3 were in agreement with the available experimental values and previous simulation results. Therefore, LiGaMD3 provides a more general and efficient approach to capture dissociation and binding of both small-molecule ligands and flexible peptides, allowing for accurate prediction of their binding thermodynamics and kinetics.
结合热力学和动力学在药物设计中起着至关重要的作用。然而,由于模拟时间尺度有限,使用传统的分子动力学(cMD)方法有效预测小分子和柔性肽的配体结合热力学和动力学具有挑战性。我们在之前开发的配体高斯加速分子动力学(LiGaMD)方法的基础上,提出了一种新的方法,称为 "LiGaMD3",其中我们在小分子/多肽解离、再结合和系统构象变化中起重要作用的三个单独的能量项中引入了三重提升,以提高小分子/多肽与目标蛋白质相互作用的采样效率。为了验证 LiGaMD3 的性能,我们选择了与小分子(Nutlin 3)结合的 MDM2 和两种高度灵活的多肽(PMI 和 P53)作为模型系统。LiGaMD3 可以在 2 μs 模拟时间内有效捕捉重复的小分子/肽解离和结合事件。LiGaMD3 预测的结合动力学常数速率和自由能与现有的实验值和以前的模拟结果一致。因此,LiGaMD3 为捕捉小分子配体和柔性多肽的解离和结合提供了一种更通用、更有效的方法,可以准确预测它们的结合热力学和动力学。
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引用次数: 0
Energetic Information from Information-Theoretic Approach in Density Functional Theory as Quantitative Measures of Physicochemical Properties. 密度泛函理论信息论方法中的能量信息作为物理化学特性的定量测量方法。
IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-12 DOI: 10.1021/acs.jctc.4c00697
Xin He, Tian Lu, Chunying Rong, Wenjian Liu, Paul W Ayers, Shubin Liu

The Hohenberg-Kohn theorem of density functional theory (DFT) stipulates that energy is a universal functional of electron density in the ground state, so energy can be thought of having encoded essential information for the density. Based on this, we recently proposed to quantify energetic information within the framework of information-theoretic approach (ITA) of DFT (J. Chem. Phys. 2022, 157, 101103). In this study, we systematically apply energetic information to a variety of chemical phenomena to validate the use of energetic information as quantitative measures of physicochemical properties. To that end, we employed six ITA quantities such as Shannon entropy and Fisher information for five energetic densities, yielding twenty-six viable energetic information quantities. Then, they are applied to correlate with physicochemical properties of molecular systems, including chemical bonding, conformational stability, intermolecular interactions, acidity, aromaticity, cooperativity, electrophilicity, nucleophilicity, and reactivity. Our results show that different quantities of energetic information often behave differently for different properties but a few of them, such as Shannon entropy of the total kinetic energy density and information gain of the Pauli energy density, stand out and strongly correlate with several properties across different categories of molecular systems. These results suggest that they can be employed as quantitative measures of physicochemical properties. This work not only enriches the body of our knowledge about the relationship between energy and information, but also provides scores of newly introduced explicit density functionals to quantify physicochemical properties, which can serve as robust features for building machine learning models in future studies.

密度泛函理论(DFT)的霍恩伯格-科恩定理(Hohenberg-Kohn theorem)规定,能量是基态电子密度的通用函数,因此可以认为能量已经编码了电子密度的基本信息。基于此,我们最近提出了在 DFT 的信息论方法(ITA)框架内量化能量信息的方法(J. Chem. Phys.)在本研究中,我们系统地将高能信息应用于各种化学现象,以验证高能信息作为物理化学性质定量指标的有效性。为此,我们针对五种能量密度采用了香农熵和费雪信息等六种 ITA 量,得出了 26 个可行的能量信息量。然后,将它们与分子体系的理化性质相关联,包括化学键、构象稳定性、分子间相互作用、酸性、芳香性、合作性、亲电性、亲核性和反应性。我们的研究结果表明,不同的能量信息量对于不同的性质往往有不同的表现,但其中少数能量信息量(如总动能密度的香农熵和保利能量密度的信息增益)比较突出,并与不同类别分子系统的若干性质密切相关。这些结果表明,它们可以用作物理化学性质的定量测量。这项工作不仅丰富了我们关于能量与信息之间关系的知识体系,还提供了数十个新引入的用于量化理化性质的显式密度函数,在未来的研究中可作为构建机器学习模型的稳健特征。
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引用次数: 0
Coarse-Grained Approach to Simulate Signatures of Excitation Energy Transfer in Two-Dimensional Electronic Spectroscopy of Large Molecular Systems. 模拟大型分子系统二维电子能谱中激发能量转移特征的粗粒度方法。
IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-12 DOI: 10.1021/acs.jctc.4c00413
Kai Zhong, Hoang Long Nguyen, Thanh Nhut Do, Howe-Siang Tan, Jasper Knoester, Thomas L C Jansen

Two-dimensional electronic spectroscopy (2DES) has proven to be a highly effective technique in studying the properties of excited states and the process of excitation energy transfer in complex molecular assemblies, particularly in biological light-harvesting systems. However, the accurate simulation of 2DES for large systems still poses a challenge because of the heavy computational demands it entails. In an effort to overcome this limitation, we devised a coarse-grained 2DES method. This method encompasses the treatment of the entire system by dividing it into distinct weakly coupled segments, which are assumed to communicate predominantly through incoherent exciton transfer. We first demonstrate the efficiency of this method through simulation on a model dimer system, which demonstrates a marked improvement in calculation efficiency, with results that exhibit good concordance with reference spectra calculated with less approximate methods. Additionally, the application of this method to the light-harvesting antenna 2 (LH2) complex of purple bacteria showcases its advantages, accuracy, and limitations. Furthermore, simulating the anisotropy decay in LH2 induced by energy transfer and its comparison with experiments confirm that the method is capable of accurately describing dynamical processes in a biologically relevant system. This method presented lends itself to an extension that accounts for the effect of intrasegment relaxation processes on the 2DES spectra, which for computational efficiency are ignored in the implementation reported here. It is envisioned that the method will be employed in the future to accurately and efficiently calculate 2D spectra of more extensive systems, such as photosynthetic supercomplexes.

二维电子能谱(2DES)已被证明是研究复杂分子组装体(尤其是生物光收集系统)激发态特性和激发能量转移过程的高效技术。然而,由于 2DES 对计算量的要求很高,因此对大型系统进行精确模拟仍然是一项挑战。为了克服这一限制,我们设计了一种粗粒度 2DES 方法。该方法将整个系统划分为不同的弱耦合片段,假定这些片段主要通过非相干激子传输进行通信。我们首先通过对模型二聚体系统的模拟来证明这种方法的效率,结果表明计算效率明显提高,与用不太近似的方法计算出的参考光谱具有很好的一致性。此外,该方法在紫色细菌的采光天线 2(LH2)复合物中的应用展示了其优势、准确性和局限性。此外,模拟由能量转移引起的 LH2 各向异性衰减及其与实验的比较证实,该方法能够准确描述生物相关系统的动态过程。所介绍的这种方法可以进行扩展,以考虑段内弛豫过程对 2DES 光谱的影响。据设想,该方法未来将用于精确、高效地计算更广泛系统的二维光谱,如光合作用超级复合物。
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引用次数: 0
Core Hole Effect to Valence Excitations: Tracking and Visualizing the Same Excitation in XPS Shake-Up Satellites and UV Absorption Spectra. 价电子激发的核孔效应:在 XPS 摇振卫星和紫外吸收光谱中跟踪和观察相同的激发。
IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-12 DOI: 10.1021/acs.jctc.4c00521
Jun-Rong Zhang, Sheng-Yu Wang, Weijie Hua

Introducing a core hole significantly alters the electronic structure of a molecule, and various X-ray spectroscopy techniques are available for probing the valence electronic structure in the presence of a core hole. In this study, we visually demonstrate the influence of a core hole on valence excitations by computing the ultraviolet absorption spectra and the shake-up satellites in X-ray photoelectron spectra for pyrrole, furan, and thiophene, as complemented by the natural transition orbital (NTO) analysis over transitions with and without a core hole. Employing equivalent core hole time-dependent density functional theory (ECH-TDDFT) and TDDFT methods, we achieved balanced accuracy in both spectra for reliable comparative analysis. We tracked the same involved valence transition in both spectra, offering a vivid illustration of the core hole effect via the change in corresponding particle NTOs introduced by a 1s core hole on a Cα, Cβ, or O atom. Our analysis deepens the understanding of the core hole effect on valence transitions, a phenomenon ubiquitously observed in general X-ray spectroscopic analyses.

核心空穴的引入会显著改变分子的电子结构,目前已有多种 X 射线光谱技术可用于探测存在核心空穴时的价电子结构。在本研究中,我们通过计算吡咯、呋喃和噻吩的紫外吸收光谱和 X 射线光电子能谱中的振荡卫星,并辅以对有无核心空穴跃迁的自然跃迁轨道(NTO)分析,直观地展示了核心空穴对价电子激发的影响。利用等效核心空穴时变密度泛函理论(ECH-TDDFT)和 TDDFT 方法,我们在两种光谱中实现了平衡精度,从而可以进行可靠的比较分析。我们在两个光谱中跟踪了相同的相关价态转变,通过 Cα、Cβ 或 O 原子上的 1s 核心空穴引入的相应粒子 NTO 的变化,生动地说明了核心空穴效应。我们的分析加深了对价态跃迁中核孔效应的理解,这是一般 X 射线光谱分析中经常观察到的现象。
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引用次数: 0
Ab Initio Prediction of Vapor Pressure for Diverse Atomic Layer Deposition Precursors 多种原子层沉积前驱体蒸气压的 Ab Initio 预测
IF 5.5 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-11 DOI: 10.1021/acs.jctc.3c01416
Alexey Odinokov, Won-Joon Son, Alexander Yakubovich, Ji Young Park, Yongsik Jung
Understanding the saturated vapor pressure (Pvap) is vital for evaluating atomic layer deposition (ALD) precursors, as it directly influences the ALD temperature window and, by extension, the processability of compounds. The early estimation of vapor pressure ranges is crucial during the initial stages of novel precursor design, reducing the reliance on empirical synthesis or experimentation. However, predicting vapor pressure through computer simulations is often impeded by the scarcity of suitable empirical force fields for molecular dynamics simulations. This challenge is further compounded by the diverse chemical substances and the introduction of new elements into modern ALD processes, necessitating robust force fields that can accommodate metals, organics, and halides. In response, this study introduces a novel approach utilizing a quantum mechanically derived force field for the prediction of vapor pressure across a wide spectrum of potential ALD precursors. This approach enables the creation of system-specific force fields through parametrization based on ab initio calculations for a single molecule. We develop a comprehensive workflow to simulate both liquid and gaseous equilibrium phases, allowing the calculation of vapor pressure across a wide temperature range. Our methodology has been validated with a diverse set of ALD precursors, demonstrating its robustness in predicting Pvap at specified temperatures. The approach yields a Pearson’s correlation coefficient (R2) greater than 0.9 on a logarithmic scale and a root-mean-squared deviation in self-solvation-free energies as low as 1.3 kcal mol–1. This innovative workflow, which does not require any prior experimental data, marks a significant advancement in the computer-aided design of novel ALD precursors, paving the way for accelerating developments in technology.
了解饱和蒸汽压 (Pvap) 对于评估原子层沉积 (ALD) 先导材料至关重要,因为它直接影响 ALD 温度窗口,进而影响化合物的加工性能。在新型前驱体设计的初始阶段,及早估算蒸汽压力范围至关重要,可减少对经验合成或实验的依赖。然而,通过计算机模拟来预测蒸气压往往会因为分子动力学模拟缺乏合适的经验力场而受到阻碍。由于化学物质的多样性以及现代 ALD 工艺中新元素的引入,这一挑战变得更加复杂,因此需要能适应金属、有机物和卤化物的强大力场。为此,本研究引入了一种新方法,利用量子力学衍生力场预测各种潜在 ALD 前驱体的蒸汽压力。这种方法可以根据单个分子的 ab initio 计算结果,通过参数化创建特定系统的力场。我们开发了一套全面的工作流程来模拟液态和气态的平衡相,从而可以计算宽温度范围内的蒸汽压力。我们的方法已通过多种 ALD 前驱体的验证,证明其在特定温度下预测 Pvap 的稳健性。该方法的对数相关系数 (R2) 大于 0.9,自溶解无能量的均方根偏差低至 1.3 kcal mol-1。这种创新的工作流程不需要任何先前的实验数据,标志着新型 ALD 前体的计算机辅助设计取得了重大进展,为加快技术发展铺平了道路。
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引用次数: 0
Rapid, Accurate, Ranking of Protein-Ligand Binding Affinities with VM2, the Second-Generation Mining Minima Method. 利用第二代最小值挖掘法 VM2 快速、准确地排列蛋白质与配体的结合亲和力。
IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Pub Date : 2024-07-11 DOI: 10.1021/acs.jctc.4c00407
Michael K Gilson, Lawrence E Stewart, Michael J Potter, Simon P Webb

The structure-based technologies most widely used to rank the affinities of candidate small molecule drugs for proteins range from faster but less reliable docking methods to slower but more accurate explicit solvent free energy methods. In recent years, we have advanced another technology, which is called mining minima because it "mines" out the main contributions to the chemical potentials of the free and bound molecular species by identifying and characterizing their main local energy minima. The present study provides systematic benchmarks of the accuracy and computational speed of mining minima, as implemented in the VeraChem Mining Minima Generation 2 (VM2) code, across two well-regarded protein-ligand benchmark data sets, for which there are already benchmark data for docking, free energy, and other computational methods. A core result is that VM2's accuracy approaches that of explicit solvent free energy methods at a far lower computational cost. In finer-grained analyses, we also examine the influence of various run settings, such as the treatment of crystallographic water molecules, on the accuracy, and define the costs in time and dollars of representative runs on Amazon Web Services (AWS) compute instances with various CPU and GPU combinations. We also use the benchmark data to determine the importance of VM2's correction from generalized Born to finite-difference Poisson-Boltzmann results for each energy well and find that this correction affords a remarkably consistent improvement in accuracy at a modest computational cost. The present results establish VM2 as a distinctive technology for early-stage drug discovery, which provides a strong combination of efficiency and predictivity.

在对候选小分子药物与蛋白质的亲和力进行排序时,最广泛使用的基于结构的技术包括速度较快但可靠性较低的对接方法,以及速度较慢但精度较高的显式溶剂自由能方法。近年来,我们推进了另一种技术,这种技术被称为 "挖掘最小值",因为它通过识别和描述自由和结合分子物种的主要局部能量最小值,"挖掘 "出它们对化学势的主要贡献。本研究对 VeraChem Mining Minima Generation 2(VM2)代码中实现的挖掘最小值的准确性和计算速度进行了系统的基准测试,测试范围是两个广受认可的蛋白质配体基准数据集,这些数据集已经有对接、自由能和其他计算方法的基准数据。一个核心结果是,VM2 的精确度接近显式溶剂自由能方法,而计算成本却低得多。在更精细的分析中,我们还研究了各种运行设置(如晶体学水分子的处理)对准确性的影响,并确定了在亚马逊网络服务(AWS)计算实例上使用各种 CPU 和 GPU 组合进行代表性运行的时间和金钱成本。我们还利用基准数据确定了 VM2 对每个能量井从广义玻恩到有限差分泊松-波尔兹曼结果进行修正的重要性,并发现这种修正以适度的计算成本显著一致地提高了精度。目前的研究结果确立了 VM2 在早期药物发现领域的独特技术地位,它是效率和预测性的有力结合。
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引用次数: 0
期刊
Journal of Chemical Theory and Computation
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