Article
Chemistry, Physical
Anita de Ruiter, Drazen Petrov, Chris Oostenbrink
Summary: The extended TI method can be used to select curves of low curvature, improving simulation efficiency. For hydration free energy calculations, an optimal parameterization is recommended. In calculations of relative binding free energies, optimized parameterizations of the Hamiltonian can effectively lower the curvature in the bound state of the ligand.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Biochemistry & Molecular Biology
Maria Conde-Gimenez, Juan Jose Galano-Frutos, Maria Galiana-Cameo, Alejandro Mahia, Bruno L. Victor, Sandra Salillas, Adrian Velazquez-Campoy, Rui M. M. Brito, Jose Antonio Galvez, Maria D. Diaz-de-Villegas, Javier Sancho
Summary: This study designs a new generation of compounds with higher affinity for phenylalanine hydroxylase (PAH) using alchemical free energy calculations. These compounds show greater stabilizing effect and bind tighter to the enzyme compared to the lead compound IV. The correspondence between calculated and experimentally determined values supports the use of this method to design pharmacological chaperones for PKU treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Marcus Wieder, Markus Fleck, Benedict Braunsfeld, Stefan Boresch
Summary: The common-core/serial-atom-insertion (CC/SAI) approach is presented for computing alchemical free energy differences between small molecules by mutating physical end-states into a suitable common core. This method, implemented in the Python package Transformato, does not require special purpose code and can be easily automated for setting up intermediate states. The method is validated by calculating relative solvation free energy differences.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2022)
Article
Computer Science, Hardware & Architecture
Salim Ullah, Hendrik Schmidl, Siva Satyendra Sahoo, Semeen Rehman, Akash Kumar
Summary: The study highlights the importance of multiplication in various applications, with accurate and approximate multiplier designs primarily proposed for ASIC systems. However, the architectural differences between ASICs and FPGA systems limit the effectiveness of these designs. A novel technique for designing signed multipliers optimized for FPGA systems is introduced to address this gap, offering improved efficiency and reduced power consumption.
IEEE TRANSACTIONS ON COMPUTERS
(2021)
Article
Chemistry, Multidisciplinary
Alice E. Brankin, Philip W. Fowler
Summary: Drug resistant Mycobacterium tuberculosis poses a major threat to tuberculosis treatment outcomes. This study used relative binding free energy (RBFE) calculations to predict the effects of mutations in M. tuberculosis RNA polymerase and DNA gyrase on the susceptibility to rifampicin and moxifloxacin, respectively. The study found that RBFE calculations can predict resistance in cases where the mutation results in a large change in binding free energy, but lacks discrimination in cases with small energy changes or involving charged amino acids.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Hsu-Chun Tsai, Tai-Sung Lee, Abir Ganguly, Timothy J. Giese, Maximilian C. C. J. C. Ebert, Paul Labute, Kenneth M. Merz, Darrin M. York
Summary: We propose a framework for optimized alchemical transformation pathways in free energy simulations using nonlinear mixing and a new functional form for softcore potentials. The framework is implemented and tested in the GPU-accelerated AMBER software suite. The optimized pathways integrate important features such as smoothstep functions, power scaling of interactions, LJ pairwise form, and smoothing of the potential at the nonbonded cutoff boundary. The pathways demonstrate superior numerical stability and minimal variance of free energy estimates compared to traditional methods.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Medicinal
Francesc Sabanes Zariquiey, Adria Perez, Maciej Majewski, Emilio Gallicchio, Gianni De Fabritiis
Summary: This study evaluates a relative binding free energy calculation method based on the alchemical transfer method (ATM). The results show that ATM is competitive in terms of speed and accuracy compared to traditional methods and can be applied with any potential energy function.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Chemistry, Physical
Michail Papadourakis, Hryhory Sinenka, Pierre Matricon, Jerome Henin, Grace Brannigan, Laura Perez-Benito, Vineet Pande, Herman van Vlijmen, Chris de Graaf, Francesca Deflorian, Gary Tresadern, Marco Cecchini, Zoe Cournia
Summary: This article reviews the progress in alchemical free energy calculations of membrane proteins, focusing on best practices and critical aspects of simulations on G-protein-coupled receptors, ion channels, transporters, and protein-lipid interactions. The study reveals the valuable application of alchemical free energy calculations in drug discovery for membrane-associated proteins.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Multidisciplinary Sciences
Zeyu Zhang, Qingde Sun, Yue Lu, Feng Lu, Xulin Mu, Su-Huai Wei, Manling Sui
Summary: The authors report hydrogenated lead-free inorganic perovskite solar cells with enhanced power conversion efficiency. By using a hydrogenation method, the bandgap of Cs2AgBiBr6 films could be tunable from 2.18 eV to 1.64 eV, resulting in improved photoelectric conversion efficiency of the solar cells.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Physical
Alexander D. Wade, Agastya P. Bhati, Shunzhou Wan, Peter Coveney
Summary: The binding free energy between a ligand and its target protein is crucial in the drug discovery process. This study examines the reproducibility of computing alchemical relative binding free energies across different molecular dynamics packages and free energy estimators. The results show good agreement between packages, indicating their consistency in calculating binding free energies.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Physical
Giorgio Domenichini, O. Anatole von Lilienfeld
Summary: In this study, we propose a method for relaxing geometries of chemical compounds using alchemical perturbation density functional theory. We provide an analytical formula for calculating mixed second order energy derivatives and implement it for relaxation of various reference and target molecules. The results show that our method yields more accurate geometries and equilibrium energies compared to standard methods.
JOURNAL OF CHEMICAL PHYSICS
(2022)
Article
Chemistry, Physical
Markus Fleck, Marcus Wieder, Stefan Boresch
Summary: In calculations of relative free energy differences, the introduction of dummy atoms is necessary to ensure that their contribution does not influence the result. It is important to make sure that dummy atoms only give a multiplicative contribution to the partition function and maintain their position and orientation relative to the physical system. The treatment of dummy atoms can have a significant impact on the computation results.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Chemistry, Physical
Yuriy Khalak, Gary Tresadern, David F. Hahn, Bert L. de Groot, Vytautas Gapsys
Summary: This research explores the combination of active learning protocol with first-principles based alchemical free energy calculations to identify high affinity PDE2 inhibitors. By explicitly evaluating only a small fraction of compounds in a large chemical library, we have successfully developed an efficient protocol.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Physical
Wei-Tse Hsu, Valerio Piomponi, Pascal T. Merz, Giovanni Bussi, Michael R. Shirts
Summary: Performing alchemical transformations is widely used in free energy calculations for biophysical processes. Alchemical methods can fail in certain scenarios, but using alchemical variables in metadynamics can enhance sampling and address these issues. In this study, alchemical metadynamics was validated and shown to accelerate sampling by introducing configurational collective variables. The necessary code changes have been released for general use in PLUMED 2.8.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Sheenam Khuttan, Solmaz Azimi, Joe Z. Wu, Emilio Gallicchio
Summary: The study introduces a family of alchemical perturbation potentials that can calculate hydration free energies of small to medium-sized molecules in a single step, instead of the usual two steps. By optimizing parameters and applying a novel soft-core function, rapid convergence of hydration free energy can be achieved in streamlined molecular dynamics simulation codes.
JOURNAL OF CHEMICAL PHYSICS
(2021)
Article
Chemistry, Physical
Hsu-Chun Tsai, Tai-Sung Lee, Abir Ganguly, Timothy J. Giese, Maximilian C. C. J. C. Ebert, Paul Labute, Kenneth M. Merz, Darrin M. York
Summary: We propose a framework for optimized alchemical transformation pathways in free energy simulations using nonlinear mixing and a new functional form for softcore potentials. The framework is implemented and tested in the GPU-accelerated AMBER software suite. The optimized pathways integrate important features such as smoothstep functions, power scaling of interactions, LJ pairwise form, and smoothing of the potential at the nonbonded cutoff boundary. The pathways demonstrate superior numerical stability and minimal variance of free energy estimates compared to traditional methods.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Jinzhe Zeng, Yujun Tao, Timothy J. Giese, Darrin M. York
Summary: We introduce the QD7 pi-v1.0 model for accurately modeling the internal energy of drug molecules. This model combines a quantum mechanical/machine learning potential correction with a high-level deep-learning potential. It outperforms other semiempirical and machine learning potentials in handling electrostatic interactions and charge/protonation state changes. The QD pi model is highly accurate in various molecular interactions and shows excellent performance in relative protonation/deprotonation energies and tautomers.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Tai-Sung Lee, Hsu-Chun Tsai, Abir Ganguly, Darrin M. York
Summary: We propose an alchemical enhanced sampling method called ACES, implemented in the GPU-accelerated AMBER free energy MD engine. The method creates an enhanced sampling state by reducing or eliminating certain potential energy terms and interactions, while maintaining terms that limit the need for extensive phase space sampling. This enhanced sampling state is connected to the real state through a Hamiltonian replica exchange framework, resulting in a counterdiffusion of states. The ACES method has been successfully applied to various test cases and demonstrated superior performance compared to traditional MD and alternative enhanced sampling methods.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Multidisciplinary
Benjamin Weissman, Solen Ekesan, Hsuan-Chun Lin, Shahbaz Gardezi, Nan-Sheng Li, Timothy J. Giese, Erika McCarthy, Michael E. Harris, Darrin M. York, Joseph A. Piccirilli
Summary: Ribonucleases and small nucleolytic ribozymes both catalyze RNA strand cleavage through 2'-O-transphosphorylation, but their mechanisms involve distinct transition states. In this study, we demonstrate that hepatitis delta virus ribozyme catalysis proceeds through a dissociative, metaphosphate-like transition state, in contrast to the associative transition states observed with other enzymes. These findings provide evidence for a unique ribozyme active site design that modulates the RNA cleavage pathway.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Suhyun Yoon, Edward Ollie, Darrin M. York, Joseph A. Piccirilli, Michael E. Harris
Summary: Psr is an important experimental system for defining RNA catalysis and designing valuable tools in biotechnology. The rate of Psr catalysis is too fast to measure manually and the reaction steps that limit catalysis are not well understood.
Article
Chemistry, Physical
Jinzhe Zeng, Yujun Tao, Timothy J. Giese, Darrin M. York
Summary: Modern semiempirical electronic structure methods have potential applications in drug discovery for accurately modeling biological and drug-like molecules. Comparisons were made between different methods, and the hybrid quantum mechanical/machine learning potentials, especially the QD pi model, showed the most robust performance for tautomers and protonation states relevant to drug discovery.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Chemistry, Physical
Timothy J. Giese, Darrin M. York
Summary: We used the modified Bigeleisen-Mayer equation to calculate kinetic isotope effect values for non-enzymatic phosphoryl transfer reactions. The modified equation includes the ratio of vibrational frequencies and the effect of isotopic substitution on the activation free energy. We developed a practical method to estimate the frequency ratio correction directly from umbrella sampling, which avoids the need for normal mode analysis. This method provides a new tool for calculating kinetic isotope effects in complex chemical reactions in the condensed phase.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Chemistry, Physical
Yuqing Xu, Michael E. Harris, Darrin M. York, Kin-Yiu Wong
Summary: RNA strand cleavage can be catalyzed by both ribozymes and hydroxide or hydronium ions. Experiments showed that cleavage of the 5'-linked nucleoside and isomerization between 3',5'- and 2',5'-phosphodiesters occur under acidic conditions, while only cleavage reaction is observed under basic conditions. A path-integral approach was used to reveal the reaction mechanisms under acidic conditions, and the proposed mechanisms can also be supported by experimental pH-rate profiles.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemistry & Molecular Biology
Erika McCarthy, Soelen Ekesan, Timothy J. Giese, Timothy J. Wilson, Jie Deng, Lin Huang, David M. J. Lilley, Darrin M. York
Summary: By using simulations and calculations, we have elucidated the mechanism of methyl transfer catalyzed by a methyltransferase ribozyme. We have identified two transition states and a rate-controlling step, and predicted the activity-pH profile of the reaction.
NUCLEIC ACIDS RESEARCH
(2023)