Article
Chemistry, Physical
Charles-Alexandre Mattelaer, Henri-Philippe Mattelaer, Jerome Rihon, Matheus Froeyen, Eveline Lescrinier
Summary: This paper demonstrates the use of HF-3c method and RI-MP2 level single point energy calculations to accurately analyze the puckering potential energy surface (PES) of DNA and RNA nucleosides, significantly reducing computational time. Applying this method to various xeno nucleic acids (XNAs) allowed for rapid exploration of the puckering PES, including the six-membered modified XNA (HNA and beta-homo-DNA) for the first time.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Chemistry, Medicinal
Bharath Raghavan, Florian K. Schackert, Andrea Levy, Sophia K. Johnson, Emiliano Ippoliti, Davide Mandelli, Jogvan Magnus Haugaard Olsen, Ursula Rothlisberger, Paolo Carloni
Summary: MiMiC is a flexible and scalable multiscale modeling framework that combines quantum mechanics (QM) and molecular mechanics (MM) codes. The paragraph introduces MiMiCPy, a user-friendly tool written in Python 3 that automates the preparation of MiMiC input files. It also highlights the modular structure of MiMiCPy, allowing for easy extensions to new program formats.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Qiang Cui, Tanmoy Pal, Luke Xie
Summary: This article discusses the challenges and issues in QM/MM simulations, emphasizing the importance of these issues for applications in biomolecular systems. Despite its limited scope, the hope is to stimulate further developments in the field of QM/MM simulation methods.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Biochemistry & Molecular Biology
Francisco Andres Peralta, J. Pablo Huidobro-Toro, Raul Mera-Adasme
Summary: QM/MM molecular dynamic simulations were used to study the allosteric modulator role of Zn(II) on P2X4R, revealing insights into the nature of Zn(II) modulation and the effects of mutations, potentially explaining elusive modulation mechanisms in other extracellular or membrane proteins.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Phujinn Honorio, Supawadee Sainimnuan, Supa Hannongbua, Patchreenart Saparpakorn
Summary: The research discovered that protoberberine alkaloids isolated from natural resources are potent inhibitors of acetylcholinesterase (AChE) and have the potential to reduce symptoms of Alzheimer's disease. The key interactions of palmatine and berberine with AChE were identified as 7C-7C interactions with specific amino acids and H-bond interactions. In contrast, cyclanoline showed a different binding mode and preference for a deeper site within AChE.
CHEMICO-BIOLOGICAL INTERACTIONS
(2021)
Article
Multidisciplinary Sciences
Zhaoxi Sun, Zhirong Liu
Summary: The study explores indirect free energy simulation methods at quantum mechanics and molecular mechanics levels, as well as attempts to optimize multi-scale treatment by changing the region for electronic structure calculations. The numerical tests show that the estimates from the indirect nonequilibrium perturbation framework are almost identical to the direct results, while the indirect equilibrium estimates deviate from the direct references.
ADVANCED THEORY AND SIMULATIONS
(2021)
Article
Chemistry, Physical
Yuzhuang Fu, Binju Wang, Zexing Cao
Summary: Detailed mechanisms for the chemical steps involved in the biodegradation of 2-oxoadipate (2OA) by HglS enzyme have been explored using MD simulations and QM/MM calculations. The study reveals the presence of two coordination modes of the Fe(IV)-oxo species, with the proximal mode responsible for C-H bond activation. Additionally, residues in the second coordination sphere play a crucial role in substrate binding and facilitate the ferryl-flip, leading to the proximal Fe(IV)-oxo conformation ideal for C-H bond activation.
JOURNAL OF CATALYSIS
(2023)
Article
Chemistry, Multidisciplinary
Ankita Tripathi, Kshatresh Dutta Dubey
Summary: This study demonstrates a method to enhance promiscuity, called allostery-driven promiscuity, using molecular dynamics simulations and hybrid QM/MM calculations. By studying the AEE enzyme, the authors show that a single site mutation can induce conformational changes in the capping loop, allowing recognition of different substrates for different functions.
CHEMISTRY-AN ASIAN JOURNAL
(2022)
Article
Chemistry, Multidisciplinary
Yuzhuang Fu, Fangfang Fan, Binju Wang, Zexing Cao
Summary: Enzymatic degradation of pesticides paraoxon (PON) and parathion (PIN) by phosphotriesterase (PTE) has been studied using QM/MM calculations and MD simulations. The results reveal that the hydrolysis reactions are driven by nucleophilic attack and the rate-limiting step is the two-step hydrolytic process.
CHEMISTRY-AN ASIAN JOURNAL
(2022)
Review
Chemistry, Medicinal
Prajakta U. Kulkarni, Harshil Shah, Vivek K. Vyas
Summary: Quantum mechanics explains the physical properties of nature at the atomic and sub-atomic level, while molecular mechanics constructs molecular systems using classical mechanics. Hybrid quantum mechanics and molecular mechanics (QM/MM) combine the accuracy of QM and the speed of MM to calculate molecular structure and property data. This method is important for studying chemical processes, protein research, and drug design.
MINI-REVIEWS IN MEDICINAL CHEMISTRY
(2022)
Article
Engineering, Multidisciplinary
Guizhong Xiao, Longfei Wen, Rong Tian
Summary: The B-spline ruled surface (BRS) method proposed in this paper successfully represents 3D cracks, achieving accuracy, numerical efficiency, and independence from mesh resolution. This method is applied in the context of Improved XFEM (IXFEM) to eliminate issues of linear dependence and ill-conditioning.
COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING
(2021)
Article
Chemistry, Physical
Vinicius Manzoni, Rogerio Gester, Antonio R. da Cunha, Tarciso Andrade-Filho, Rodrigo Gester
Summary: The analysis of solvent effects on the fluorescence and NLO response of thieno[3,4-b]pyrazine was done using s-MC/QM method, showing potential applications in solar cells and biological markers. EC plays a key role in the first hyperpolarizability, with solvent effects being negligible.
JOURNAL OF MOLECULAR LIQUIDS
(2021)
Article
Chemistry, Physical
Julian Boeser, Tomas Kubar, Marcus Elstner, Denis Maag
Summary: This study investigates the mechanism of glutaredoxin catalyzed oxidation and reduction of protein disulfide bonds through both experimental and computational approaches. Molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical metadynamics simulations were used to obtain the free energy profiles of the reactions. The results confirm the proposed pathway and provide insights into the regiospecificity of the reactions.
JOURNAL OF CHEMICAL PHYSICS
(2022)
Article
Chemistry, Physical
Severin Polonius, Oleksandra Zhuravel, Brigitta Bachmair, Sebastian Mai
Summary: We present a theoretical framework, called the linear vibronic coupling/molecular mechanics (LVC/MM) method, for embedding a hybrid linear vibronic coupling model electrostatically into a molecular mechanics environment. Electrostatic embedding is achieved through the computation of interactions between environment point charges and distributed multipole expansions. By testing with thioformaldehyde in water, we demonstrate that LVC/MM can accurately reproduce the solvation structure and energetics of rigid solutes.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemistry & Molecular Biology
Sijin Chen, Xiaoyan Ding, Chao Sun, Anthony Watts, Xiao He, Xin Zhao
Summary: The study investigated the dynamic coupling of Y185 with the bR photocycle through calculations and simulations, revealing its significant role in regulating thermal equilibrium, stabilizing H-bond networks, participating in orientation switch, and opening the channel gate. These findings provide a detailed molecular mechanism of the dynamic couplings of Y185 and the bR photocycle from a structural perspective, with potential applications to other microbial photoreceptors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Tushar Aggarwal, William A. Hansen, Jonathan Hong, Abir Ganguly, Darrin M. York, Sagar D. Khare, Enver Cagri Izgu
Summary: Researchers have redesigned an archaeal DNA polymerase to exhibit a new activity of catalyzing the formation of internucleotidyl N-P linkages. This unnatural enzyme activity was enabled by a key substitution in the active site, which enhanced the positioning of a 3'-amino nucleophile. Further modifications of the protein-nucleic acid interface yielded a variant with DNA-dependent NP-DNA polymerase activity, which was utilized for the synthesis of DNA-NP-DNA copolymers. This study provides insights into substrate fidelity and latent promiscuity in enzymes.
ACS CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Physical
Timothy J. Giese, Jinzhe Zeng, Solen Ekesan, Darrin M. York
Summary: This paper presents a fast, accurate, and robust approach for determining free energy profiles and kinetic isotope effects of RNA reactions with the inclusion of nuclear quantum effects. The approach utilizes deep potential range correction (DPRc) and quantum mechanical/molecular mechanical (QM/MM) simulations to achieve high accuracy in tuning QM and QM/MM interactions. The method is demonstrated through the calculation of free energy profiles of RNA cleavage reactions and reactions involving thio-substitutions, showing close agreement with ab initio calculations and the superior performance compared to other methods.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Physical
Solen Ekesan, Erika McCarthy, David A. Case, Darrin M. York
Summary: Electrostatic interactions play a crucial role in the structure and function of RNA, particularly in the recruitment of metal ions for catalysis. This study investigates the electrostatic features and their relation to the binding of monovalent and divalent metal ions in metal-dependent ribozymes and an engineered DNAzyme. The findings demonstrate the importance of RNA electrostatics in catalysis, including the structural integrity of the active state, pK(a) tuning, and electrostatic stabilization of the transition state.
JOURNAL OF PHYSICAL CHEMISTRY B
(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, 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)
Article
Biochemistry & Molecular Biology
Erich R. Kuechler, Matthew Jacobson, Thibault Mayor, Jorg Gsponer
Summary: Phase separation-based condensate formation is an important phenomenon in biology, and the GraPES web-server provides propensity scores for the localization of proteins into cellular condensates, which helps uncover the functional impact of these condensates.
NUCLEIC ACIDS RESEARCH
(2022)