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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
Journal of Chemical Theory and Computation Pub Date : 2024-07-13 DOI: 10.1021/acs.jctc.4c00502
Jinan Wang, Yinglong Miao
{"title":"Ligand Gaussian Accelerated Molecular Dynamics 3 (LiGaMD3): Improved Calculations of Binding Thermodynamics and Kinetics of Both Small Molecules and Flexible Peptides","authors":"Jinan Wang, Yinglong Miao","doi":"10.1021/acs.jctc.4c00502","DOIUrl":"https://doi.org/10.1021/acs.jctc.4c00502","url":null,"abstract":"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.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Chemical Theory and Computation Pub Date : 2024-07-12 DOI: 10.1021/acs.jctc.4c00697
Xin He, Tian Lu, Chunying Rong, Wenjian Liu, Paul W Ayers, Shubin Liu
{"title":"Energetic Information from Information-Theoretic Approach in Density Functional Theory as Quantitative Measures of Physicochemical Properties.","authors":"Xin He, Tian Lu, Chunying Rong, Wenjian Liu, Paul W Ayers, Shubin Liu","doi":"10.1021/acs.jctc.4c00697","DOIUrl":"https://doi.org/10.1021/acs.jctc.4c00697","url":null,"abstract":"<p><p>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 (<i>J. Chem. Phys</i>. <b>2022</b>, 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.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Chemical Theory and Computation 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
{"title":"Coarse-Grained Approach to Simulate Signatures of Excitation Energy Transfer in Two-Dimensional Electronic Spectroscopy of Large Molecular Systems.","authors":"Kai Zhong, Hoang Long Nguyen, Thanh Nhut Do, Howe-Siang Tan, Jasper Knoester, Thomas L C Jansen","doi":"10.1021/acs.jctc.4c00413","DOIUrl":"https://doi.org/10.1021/acs.jctc.4c00413","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Chemical Theory and Computation Pub Date : 2024-07-12 DOI: 10.1021/acs.jctc.4c00521
Jun-Rong Zhang, Sheng-Yu Wang, Weijie Hua
{"title":"Core Hole Effect to Valence Excitations: Tracking and Visualizing the Same Excitation in XPS Shake-Up Satellites and UV Absorption Spectra.","authors":"Jun-Rong Zhang, Sheng-Yu Wang, Weijie Hua","doi":"10.1021/acs.jctc.4c00521","DOIUrl":"https://doi.org/10.1021/acs.jctc.4c00521","url":null,"abstract":"<p><p>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 C<sub>α</sub>, C<sub>β</sub>, 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.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Chemical Theory and Computation Pub Date : 2024-07-11 DOI: 10.1021/acs.jctc.3c01416
Alexey Odinokov, Won-Joon Son, Alexander Yakubovich, Ji Young Park, Yongsik Jung
{"title":"Ab Initio Prediction of Vapor Pressure for Diverse Atomic Layer Deposition Precursors","authors":"Alexey Odinokov, Won-Joon Son, Alexander Yakubovich, Ji Young Park, Yongsik Jung","doi":"10.1021/acs.jctc.3c01416","DOIUrl":"https://doi.org/10.1021/acs.jctc.3c01416","url":null,"abstract":"Understanding the saturated vapor pressure (<i>P</i><sub>vap</sub>) 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 <i>ab initio</i> 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 <i>P</i><sub>vap</sub> at specified temperatures. The approach yields a Pearson’s correlation coefficient (<i>R</i><sup>2</sup>) 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<sup>–1</sup>. 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.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Chemical Theory and Computation Pub Date : 2024-07-11 DOI: 10.1021/acs.jctc.4c00407
Michael K Gilson, Lawrence E Stewart, Michael J Potter, Simon P Webb
{"title":"Rapid, Accurate, Ranking of Protein-Ligand Binding Affinities with VM2, the Second-Generation Mining Minima Method.","authors":"Michael K Gilson, Lawrence E Stewart, Michael J Potter, Simon P Webb","doi":"10.1021/acs.jctc.4c00407","DOIUrl":"10.1021/acs.jctc.4c00407","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Influence of the Water Model on the Structure and Interactions of the GPR40 Protein with the Lipid Membrane and the Solvent: Rigid versus Flexible Water Models 水模型对 GPR40 蛋白结构以及与脂膜和溶剂相互作用的影响:刚性与柔性水模型
IF 5.5 1区 化学
Journal of Chemical Theory and Computation Pub Date : 2024-07-11 DOI: 10.1021/acs.jctc.4c00571
Jorge Alberto Aguilar-Pineda, Minerva González-Melchor
{"title":"Influence of the Water Model on the Structure and Interactions of the GPR40 Protein with the Lipid Membrane and the Solvent: Rigid versus Flexible Water Models","authors":"Jorge Alberto Aguilar-Pineda, Minerva González-Melchor","doi":"10.1021/acs.jctc.4c00571","DOIUrl":"https://doi.org/10.1021/acs.jctc.4c00571","url":null,"abstract":"G protein-coupled receptors (GPCR) are responsible for modulating various physiological functions and are thus related to the pathophysiology of different diseases. Being potential therapeutic targets, multiple computational methodologies have been developed to analyze their behavior and interactions with other species. The solvent, on the other hand, has received much less attention. In this work, we analyzed the effect of four explicit water models on the structure and interactions of the GPR40 receptor in its apo form. We employed the rigid SPC/E and TIP4P models, and their flexible versions, the FBA/ϵ and TIP4P/ϵ<sub>flex</sub>. We explored the structural changes and their correlation with some bulk dynamic properties of water. Our results showed an adverse effect on the conservation of the secondary structure of the receptor with all the models due to the breaking of the intramolecular hydrogen bond network, being more evident for the TIP4P models. Notably, all four models brought the receptor to states similar to the active one, modifying the intracellular part of the TM5 and TM6 domains in a “hinge” type movement, allowing the opening of the structure. Regarding the dynamic properties, the rigid models showed results comparable to those obtained in other studies on membrane systems. However, flexible models exhibit disparities in the molecular representation of systems. Surprisingly, the FBA/ϵ model improves the molecular picture of several properties, even though their agreement with bulk diffusion is poorer. These findings reinforce our idea that exploring other water models or improving the current ones, to better represent the membrane interface, can lead to a positive impact on the description of the signal transduction mechanisms and the search of new drugs by targeting these receptors.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Efficient Parameterization of Density Functional Tight-Binding for 5f-Elements: A Th–O Case Study 5f 元素密度函数紧密结合的高效参数化:Th-O 案例研究
IF 5.5 1区 化学
Journal of Chemical Theory and Computation Pub Date : 2024-07-11 DOI: 10.1021/acs.jctc.4c00145
Chang Liu, Néstor F. Aguirre, Marc J. Cawkwell, Enrique R. Batista, Ping Yang
{"title":"Efficient Parameterization of Density Functional Tight-Binding for 5f-Elements: A Th–O Case Study","authors":"Chang Liu, Néstor F. Aguirre, Marc J. Cawkwell, Enrique R. Batista, Ping Yang","doi":"10.1021/acs.jctc.4c00145","DOIUrl":"https://doi.org/10.1021/acs.jctc.4c00145","url":null,"abstract":"Density functional tight binding (DFTB) models for <i>f</i>-element species are challenging to parametrize owing to the large number of adjustable parameters. The explicit optimization of the terms entering the semiempirical DFTB Hamiltonian related to <i>f</i> orbitals is crucial to generating a reliable parametrization for <i>f</i>-block elements, because they play import roles in bonding interactions. However, since the number of parameters grows quadratically with the number of orbitals, the computational cost for parameter optimization is much more expensive for the <i>f</i>-elements than for the main group elements. In this work we present a set of efficient approaches for mitigating the hurdle imposed by the large size of the parameter space. A novel group-by-orbital correction functions for two-center bond integrals was developed. With this approach the number of parameters is reduced, and it grows linearly with the number of elements, maintaining the accuracy and the number of parameters, in the case of f elements, by more than 40%. The parameter optimization step was accelerated by means of the mini-batch BFGS method. This method allows parameter optimizations with much larger training sets than other single batch methods. A stochastic optimizer was employed that helped overcome shallow local minima in the objective function. The proposed algorithm was used to parametrize the DFTB Hamiltonian for the Th–O system, which was subsequently applied to the study of ThO<sub>2</sub> nanoparticles. The training set consisted of 6322 unique structures, which is barely feasible with conventional optimization methods. The optimized parameter set, <i>LANL-ThO</i>, displays good agreement with DFT-calculated properties such as energies, forces, and structures for both clusters and bulk ThO<sub>2</sub>. Benefiting from the fewer number of parameters and lower computational costs for objective function evaluations, this new approach shows its potential applications in DFTB parametrization for elements with high angular momentum, which present a challenge to conventional methods.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Calculating Protein–Ligand Residence Times through State Predictive Information Bottleneck Based Enhanced Sampling 通过基于状态预测信息瓶颈的增强采样计算蛋白质配体停留时间
IF 5.5 1区 化学
Journal of Chemical Theory and Computation Pub Date : 2024-07-11 DOI: 10.1021/acs.jctc.4c00503
Suemin Lee, Dedi Wang, Markus A. Seeliger, Pratyush Tiwary
{"title":"Calculating Protein–Ligand Residence Times through State Predictive Information Bottleneck Based Enhanced Sampling","authors":"Suemin Lee, Dedi Wang, Markus A. Seeliger, Pratyush Tiwary","doi":"10.1021/acs.jctc.4c00503","DOIUrl":"https://doi.org/10.1021/acs.jctc.4c00503","url":null,"abstract":"Understanding drug residence times in target proteins is key to improving drug efficacy and understanding target recognition in biochemistry. While drug residence time is just as important as binding affinity, atomic-level understanding of drug residence times through molecular dynamics (MD) simulations has been difficult primarily due to the extremely long time scales. Recent advances in rare event sampling have allowed us to reach these time scales, yet predicting protein–ligand residence times remains a significant challenge. Here we present a semi-automated protocol to calculate the ligand residence times across 12 orders of magnitude of time scales. In our proposed framework, we integrate a deep learning-based method, the state predictive information bottleneck (SPIB), to learn an approximate reaction coordinate (RC) and use it to guide the enhanced sampling method metadynamics. We demonstrate the performance of our algorithm by applying it to six different protein–ligand complexes with available benchmark residence times, including the dissociation of the widely studied anticancer drug Imatinib (Gleevec) from both wild-type Abl kinase and drug-resistant mutants. We show how our protocol can recover quantitatively accurate residence times, potentially opening avenues for deeper insights into drug development possibilities and ligand recognition mechanisms.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Assessing the Accuracy and Efficiency of Free Energy Differences Obtained from Reweighted Flow-Based Probabilistic Generative Models. 评估从基于重加权流的概率生成模型中获得的自由能差的准确性和效率。
IF 5.7 1区 化学
Journal of Chemical Theory and Computation Pub Date : 2024-07-10 DOI: 10.1021/acs.jctc.4c00520
Edgar Olehnovics, Yifei Michelle Liu, Nada Mehio, Ahmad Y Sheikh, Michael R Shirts, Matteo Salvalaglio
{"title":"Assessing the Accuracy and Efficiency of Free Energy Differences Obtained from <i>Reweighted</i> Flow-Based Probabilistic Generative Models.","authors":"Edgar Olehnovics, Yifei Michelle Liu, Nada Mehio, Ahmad Y Sheikh, Michael R Shirts, Matteo Salvalaglio","doi":"10.1021/acs.jctc.4c00520","DOIUrl":"https://doi.org/10.1021/acs.jctc.4c00520","url":null,"abstract":"<p><p>Computing free energy differences between metastable states characterized by nonoverlapping Boltzmann distributions is often a computationally intensive endeavor, usually requiring chains of intermediate states to connect them. Targeted free energy perturbation (TFEP) can significantly lower the computational cost of FEP calculations by choosing a set of invertible maps used to directly connect the distributions of interest, achieving the necessary statistically significant overlaps without sampling any intermediate states. Probabilistic generative models (PGMs) based on normalizing flow architectures can make it much easier via machine learning to train invertible maps needed for TFEP. However, the accuracy and applicability of approaches based on empirically learned maps depend crucially on the choice of reweighting method adopted to estimate the free energy differences. In this work, we assess the accuracy, rate of convergence, and data efficiency of different free energy estimators, including exponential averaging, Bennett acceptance ratio (BAR), and multistate Bennett acceptance ratio (MBAR), in reweighting PGMs trained by maximum likelihood on limited amounts of molecular dynamics data sampled only from end-states of interest. We carry out the comparisons on a set of simple but representative case studies, including conformational ensembles of alanine dipeptide and ibuprofen. Our results indicate that BAR and MBAR are both data efficient and robust, even in the presence of significant model overfitting in the generation of invertible maps. This analysis can serve as a stepping stone for the deployment of efficient and quantitatively accurate ML-based free energy calculation methods in complex systems.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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