Article
Biochemistry & Molecular Biology
Mehtap Isik, Arien S. Rustenburg, Andrea Rizzi, M. R. Gunner, David L. Mobley, John D. Chodera
Summary: The prediction of pK(a) is essential for predicting various properties of small molecules. The SAMPL6 pK(a) Challenge assessed contemporary prediction methods, highlighting the need for improvement in predicting microstate and macrostate pK(a) values, especially for challenging molecules with multiple protonation sites. Achieving accurate predictions is crucial for protein-ligand binding affinity calculations.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2021)
Article
Chemistry, Medicinal
Robert Fraczkiewicz, Marvin Waldman
Summary: In this study, it is shown that the apparent pKa measured through standard titration experiments is not sufficient to accurately assess the acidity/basicity of organic functional groups in multiprotic compounds, which is a common situation in pharmaceutical research. The use of apparent pKa in such cases may lead to costly errors. To address this issue, the authors propose pK50 as a single-proton midpoint measure, derived from a statistical thermodynamics treatment of multiprotic ionization. The study demonstrates that pK50, which can be directly measured using specialized NMR titration experiments, is superior in tracking the acidity/basicity of the functional groups across related compounds and converges to the ionization constant in the monoprotic case.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Teresa Danielle Bergazin, Nicolas Tielker, Yingying Zhang, Junjun Mao, M. R. Gunner, Karol Francisco, Carlo Ballatore, Stefan M. Kast, David L. Mobley
Summary: The SAMPL7 challenge assessed the accuracy of predicting octanol-water partition coefficients and pK(a), with lower accuracy in log P predictions compared to SAMPL6 and unchanged accuracy in pK(a) predictions. Participants often disagreed on the microscopic transitions producing macroscopic pK(a) values, indicating a need for further improvement in pK(a) prediction methods.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2021)
Article
Multidisciplinary Sciences
Sabrina Huth, Peter T. H. Pang, Ingo Tews, Tim Dietrich, Arnaud Le Fevre, Achim Schwenk, Wolfgang Trautmann, Kshitij Agarwal, Mattia Bulla, Michael W. Coughlin, Chris Van den Broeck
Summary: Studying dense matter is crucial for understanding high-energy astrophysical phenomena, and data from heavy-ion collision experiments provide valuable insights in addition to astrophysical observations. By combining data from various sources, including heavy-ion collisions and microscopic nuclear theory calculations, researchers found significant improvements in their understanding of dense matter and its consistency with observations.
Article
Biochemistry & Molecular Biology
Matthew N. Bahr, Aakankschit Nandkeolyar, John K. Kenna, Neysa Nevins, Luigi Da Via, Mehtap Isik, John D. Chodera, David L. Mobley
Summary: The SAMPL challenge aims to improve the accuracy of computational models in predicting the physical properties of pharmaceutical compounds. This study utilizes experimental datasets and high throughput equipment to provide a comprehensive data set for blind prediction challenges.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2021)
Article
Chemistry, Analytical
Matthew Wallace, Nduchi Abiama, Miranda Chipembere
Summary: This paper presents a method to directly determine the acid dissociation constant (pK(a)) in aqueous-organic solvents using nuclear magnetic resonance (NMR). By measuring the chemical shift of an organic acid as a function of concentration and using it as a reference, the pK(a) values of less acidic molecules can be determined. The method was successfully applied to determine the pK(a) values of organic acids and bases in different aqueous-organic solvent mixtures, and the results were in good agreement with literature values.
ANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Pedro B. P. S. Reis, Marco Bertolini, Floriane Montanari, Walter Rocchia, Miguel Machuqueiro, Djork-Arne Clevert
Summary: In this study, deep learning models trained on a dataset of 6 million theoretically determined pK(a) shifts successfully inferred the electrostatic contributions of different chemical groups and the importance of solvent exposure. The models demonstrated the best accuracy in a test set and significantly outperformed physics-based methods in terms of inference speed.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Physical
Nguyen Q. Vinh, Luan C. Doan, Ngoc L. H. Hoang, Jiarong R. R. Cui, Ben Sindle
Summary: Water is essential for life, as it plays a crucial role in maintaining the structure and function of biomolecules and cells. The unique properties of water, such as its ability to form hydrogen bonds and dynamic networks, contribute to its remarkable characteristics. Experimental investigation of water dynamics is challenging due to its strong absorption at terahertz frequencies. However, using a high-precision terahertz spectrometer, researchers have successfully measured and characterized the terahertz dielectric response of water, providing insights into its motion and relaxation processes. The findings reveal a direct relationship between macroscopic and microscopic relaxation dynamics, supporting the existence of two liquid forms in water with different transition temperatures and thermal activation energies. These results offer an unprecedented opportunity to validate microscopic computational models of water dynamics.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Energy & Fuels
Theophile Gaudin, Jean-Marie Aubry
Summary: Redox-flow batteries are used to store energy from intermittent sources like solar panels or wind turbines. Most of these batteries are based on vanadium, which is rare and expensive. Recent research has focused on using organic compounds, particularly anthraquinones, as electroactive materials for redox-flow batteries. However, finding organic compounds with the desired electrochemical properties is challenging due to the tunability of organic chemistry. Additionally, the low water solubility of readily available anthraquinones may limit their use as battery electrolytes. This study proposes a theoretical approach to predict the behavior of redox-active organic compounds using Pourbaix diagrams. The predictions from this method are in good agreement with experimental data, demonstrating its reliability. Furthermore, the study explores the impact of functional groups on the anthraquinone structure, highlighting the method's ability to understand and quantify the electrochemical activity of redox-active organic materials.
JOURNAL OF ENERGY STORAGE
(2022)
Article
Chemistry, Inorganic & Nuclear
Aohan Hu, Megan E. Simms, Vilmos Kertesz, Justin J. Wilson, Nikki A. Thiele
Summary: Radioisotopes of metallic elements, or radiometals, are widely used in nuclear medicine. Recently, a new class of macrocyclic chelators with dual size selectivity was reported. A specific chelator called py(2)-macrodipa was found to have enhanced thermodynamic affinity for Ln(3+) and improved kinetic stability for light, large Ln(3+) ions. Moreover, py(2)-macrodipa was shown to effectively incorporate Ac-225(3+) and form a stable complex in human serum.
INORGANIC CHEMISTRY
(2022)
Article
Thermodynamics
Amirali Rezazadeh, Kaj Thomsen, Hariklia N. Gavala, Ioannis Skiadas, Philip L. Fosbol
Summary: The solubility of disodium terephthalate in aqueous sodium hydroxide and in aqueous sodium hydroxide-ethylene glycol mixtures was experimentally determined, and its phase diagrams were established from -25 to 70 degrees C. The solubility of disodium terephthalate shows no significant dependence on temperature, while its freezing points vary with composition. The solubility and freezing points decrease with increasing concentrations of ethylene glycol, and disodium terephthalate is salted out by the addition of sodium hydroxide.
JOURNAL OF CHEMICAL AND ENGINEERING DATA
(2021)
Article
Chemistry, Medicinal
Wanlei Wei, Hervei Hogues, Traian Sulea
Summary: The demand for protein engineering in different pH environments has driven the development of computational algorithms to evaluate large sets of protein residues and point mutations. This study systematically tested seven fast and accessible approaches and found that DeepKa, PKAI+, PROPKA3, and H++ performed well. Combining the best empirical predictors into simple consensuses improved the overall accuracy and transferability.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Organic
Sai Shradha Reddy Kommidi, Bradley D. Smith
Summary: This report investigates the complexation of azobenzenedyes with cucurbit[7]uril (CB7). The results show that CB7 encapsulates the protonated form of the azobenzene and stabilizes the dye conjugate acid, leading to an increase in pK(a). Molecular modeling suggests that this complex formation is stabilized by ion-dipole interactions, inclusion of the azobenzene ring within the CB7 cavity, and a hydrogen bond between the azo nitrogen and CB7 carbonyls. CB7 complexation not only enhances the stability and hydrophilicity of azobenzene but also offers potential applications in pigment and prodrug development, as well as creating dye displacement assays.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Lucie Nytrova, Klara Odehnalova, Jiri Pazourek
Summary: This study extends the applicability of the internal standard method published in 2009, demonstrating that the original capillary zone electrophoresis method can effectively overcome analyte interactions in mixed solvents. The extended method is illustrated on six selected beta-blockers.
Article
Physics, Nuclear
Marc Verriere, Matthew Ryan Mumpower
Summary: In this work, enhancements to the well-established macroscopic-microscopic description of nuclear fission are presented, including improvements to the microscopic sector, a novel deterministic method for fission dynamics, and the calculation of fission fragments mass and charge distributions using particle number projection. These enhancements result in successful predictions of odd-even staggering and charge polarization for the neutron-induced fission of U-233 and U-235.
Article
Chemistry, Medicinal
Gregory L. Adams, Parul S. Pall, Steven M. Grauer, Xiaoping Zhou, Jeanine E. Ballard, Marissa Vavrek, Richard L. Kraus, Pierre Morissette, Nianyu Li, Stefania Colarusso, Elisabetta Bianchi, Anandan Palani, Rebecca Klein, Christopher T. John, Deping Wang, Matthew Tudor, Andrew F. Nolting, Mirlinda Biba, Timothy Nowak, Alexey A. Makarov, Mikhail Reibarkh, Alexei Buevich, Wendy Zhong, Erik L. Regalado, Xiao Wang, Qi Gao, Aurash Shahripour, Yuping Zhu, Daniele de Simone, Tommaso Frattarelli, Nicolo' Maria Pasquini, Paola Magotti, Roberto Iaccarino, Yuxing Li, Kelli Solly, Keun-Joong Lee, Weixun Wang, Feifei Chen, Haoyu Zeng, Jixin Wang, Hilary Regan, Rupesh P. Amin, Christopher P. Regan, Christopher S. Burgey, Darrell A. Henze, Chengzao Sun, David M. Tellers
Summary: Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Na(v)1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Analytical
Debopreeti Mukherjee, Pablo Trigo-Mourino, Yuan Jiang, Timothy Nowak, Vladimir Shchurik, Donovon A. Adpressa, Michael T. Louie, Shane R. Reynolds, Michael J. Hohn, Mohammad Ahmed Al-Sayah, Gregory F. Pirrone, Alexey A. Makarov
Summary: Recent advances in cancer biology have accelerated the discovery and development of novel biopharmaceuticals. A study utilizing matrix-assisted laser desorption/ionization mass spectrometry and hydrogen-deuterium exchange mass spectrometry demonstrated the rapid conformational characterization of monoclonal and bi-specific antibodies, showcasing the potential of this methodology in the field.
JOURNAL OF SEPARATION SCIENCE
(2022)
Article
Chemistry, Multidisciplinary
Xingshuo Chen, Zhenwei Wei, Kai-Hung Huang, Mycah Uehling, Michael Wleklinski, Shane Krska, Alexey A. Makarov, Timothy Nowak, R. Graham Cooks
Summary: In this study, nanoelectrospray ionization mass spectrometry (nanoESI-MS) was used to monitor the precatalysts, catalytic intermediates, reagents, and products of the Suzuki-Miyaura cross-coupling reaction. Pd cluster ions related to the active catalyst and an oxidized catalyst were detected, with the latter increasing as the reaction proceeds. Further experiments confirmed the presence of the oxidized catalyst. Monitoring the formation and conversion of the oxidative addition intermediate provided insights into the progress of the transmetalation step in the catalytic cycle.
Article
Chemistry, Physical
Simon Boothroyd, Owen C. Madin, David L. Mobley, Lee-Ping Wang, John D. Chodera, Michael R. Shirts
Summary: This study demonstrates that including physical property data of binary mixtures can improve the accuracy of classical force field models for complex chemical mixtures, correcting some errors that occur when training van der Waals interactions based solely on properties of pure systems.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biochemistry & Molecular Biology
Harold Grosjean, Mehtap Isik, Anthony Aimon, David Mobley, John Chodera, Frank von Delft, Philip C. Biggin
Summary: A novel crystallographic fragment screening data set was generated and used in the SAMPL7 challenge for protein-ligands. The results show that there is room for improvement in the development of computational tools particularly when applied to fragment-based drug design.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2022)
Review
Chemistry, Multidisciplinary
Suzanne Ackloo, Rima Al-awar, Rommie E. Amaro, Cheryl H. Arrowsmith, Hatylas Azevedo, Robert A. Batey, Yoshua Bengio, Ulrich A. K. Betz, Cristian G. Bologa, John D. Chodera, Wendy D. Cornell, Ian Dunham, Gerhard F. Ecker, Kristina Edfeldt, Aled M. Edwards, Michael K. Gilson, Claudia R. Gordijo, Gerhard Hessler, Alexander Hillisch, Anders Hogner, John J. Irwin, Johanna M. Jansen, Daniel Kuhn, Andrew R. Leach, Alpha A. Lee, Uta Lessel, Maxwell R. Morgan, John Moult, Ingo Muegge, Tudor Oprea, Benjamin G. Perry, Patrick Riley, Sophie A. L. Rousseaux, Kumar Singh Saikatendu, Vijayaratnam Santhakumar, Matthieu Schapira, Cora Scholten, Matthew H. Todd, Masoud Vedadi, Andrea Volkamer, Timothy M. Willson
Summary: One goal of computational chemistry is to improve small-molecule hit-finding algorithms through prediction and experimental testing. CACHE is a public benchmarking project that evaluates and compares computational approaches, aiming to discover new small-molecule binders for important protein targets.
NATURE REVIEWS CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Anna Fryszkowska, Chihui An, Oscar Alvizo, Goutami Banerjee, Keith A. Canada, Yang Cao, Duane DeMong, Paul N. Devine, Da Duan, David M. Elgart, Iman Farasat, Donald R. Gauthier, Erin N. Guidry, Xiujuan Jia, Jongrock Kong, Nikki Kruse, Katrina W. Lexa, Alexey A. Makarov, Benjamin F. Mann, Erika M. Milczek, Vesna Mitchell, Jovana Nazor, Claudia Neri, Robert K. Orr, Peter Orth, Eric M. Phillips, James N. Riggins, Wes A. Schafer, Steven M. Silverman, Christopher A. Strulson, Nandhitha Subramanian, Rama Voladri, Hao Yang, Jie Yang, Xiang Yi, Xiyun Zhang, Wendy Zhong
Summary: This article introduces a bioconjugation strategy for selectively modifying native peptides using high site selectivity conveyed by engineered enzymes. By modifying certain amino groups and cleavable phenylacetamide groups in insulin, homogeneous bioconjugates with improved yield and purity were synthesized.
Article
Chemistry, Analytical
Alexey A. Makarov, Yuan Jiang, Christopher Sondey, Minjia Zhang, My Sam Mansueto, Gregory F. Pirrone, Chunhui Huang, Kaustav Biswas, Ruchia Duggal, Mohammad Ahmed Al-Sayah, Erik L. Regalado, Ian Mangion
Summary: This study demonstrates the development of a rapid high-throughput label-free methodology for evaluating peptide cell membrane permeability, applied to a range of 24 diverse peptides, with results consistent with literature data. The methodology, known as CAMPA, utilizes a MALDI-HDX-MS approach and automated MS data processing using Python scripts. Additionally, CAMPA was shown to differentiate passive and active cell transportation by using endocytosis inhibitor in cell incubation media for selected peptides.
ANALYTICA CHIMICA ACTA
(2022)
Article
Chemistry, Medicinal
Joshua T. Horton, Simon Boothroyd, Jeffrey Wagner, Joshua A. Mitchell, Trevor Gokey, David L. Dotson, Pavan Kumar Behara, Venkata Krishnan Ramaswamy, Mark Mackey, John D. Chodera, Jamshed Anwar, David L. Mobley, Daniel J. Cole
Summary: The development of accurate transferable force fields is essential for maximizing the potential of atomistic modeling in studying biological processes. This study presents software packages for fitting torsion parameters to quantum mechanical reference data, and demonstrates significant improvements in accuracy by using bespoke force fields.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Physical
Oliver J. Melling, Marley L. Samways, Yunhui Ge, David L. Mobley, Jonathan W. Essex
Summary: Water molecules are crucial in biomolecular systems, especially at protein-ligand interfaces. However, simulating such systems is challenging due to slow water exchange between protein and solvent. To overcome this, the authors combine grand canonical Monte Carlo (GCMC) with nonequilibrium candidate Monte Carlo (NCMC) to develop grand canonical nonequilibrium candidate Monte Carlo (GCNCMC). This approach improves water sampling efficiency and enables the exploration of new ligand-binding geometries mediated by water.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemical Research Methods
David C. Wych, Phillip C. Aoto, Lily Vu, Alexander M. Wolff, David L. Mobley, James S. Fraser, Susan S. Taylor, Michael E. Wall
Summary: This article investigates the use of molecular-dynamics (MD) simulations to improve macromolecular crystallography (MX) studies. By combining MD simulations with conventional modeling and refinement tools, the authors were able to improve the interpretation of ambiguous density in protein crystals, leading to more accurate protein models and mechanistic insights into enzyme interactions.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Mary Pitman, David F. Hahn, Gary Tresadern, David L. Mobley
Summary: Drug discovery is accelerated using computational methods such as alchemical simulations to estimate ligand affinities. Recent research shows that optimizing the statistical architecture of perturbation graphs improves the accuracy of predicted changes in ligand binding energy. To improve the success rate of computational drug discovery, we present the open-source software package HiMap, which is a new version of its predecessor LOMAP.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Hannah M. Baumann, Eric Dybeck, Christopher L. McClendon, Frank C. Pickard, Vytautas Gapsys, Laura Perez-Benito, David F. Hahn, Gary Tresadern, Alan M. Mathiowetz, David L. Mobley
Summary: Binding free energy calculations are used to predict the potency of compounds binding to protein sites in a physically rigorous manner. Relative binding free energy (RBFE) calculations are commonly used but limited by the requirement of ligands sharing a common scaffold and binding mode. Absolute binding free energy (ABFE) calculations are an alternate method for non-congeneric ligands but suffer from long convergence times. The SepTop method overcomes the limitations of both RBFE and ABFE methods by allowing large scaffold changes between ligands with comparable convergence time. It provides a more efficient and flexible approach for ranking ligands in drug design.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Ivy Zhang, Dominic A. Rufa, Ivan Pulido, Michael M. Henry, Laura E. Rosen, Kevin Hauser, Sukrit Singh, John D. Chodera
Summary: Relative alchemical binding free energy calculations are used for drug discovery and protein:protein binding affinity estimation. This study investigates the sampling challenges in protein:protein relative free energy calculations and explores the accuracy and efficiency of current approaches. The research provides a model workflow for protein mutation free energy calculations and catalogues the sampling challenges. The developed open-source package (Perses) achieves accurate predictions with high classification rate of binding free energy changes.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemistry & Molecular Biology
Yen-Pang Hsu, Martin Frank, Debopreeti Mukherjee, Vladimir Shchurik, Alexey Makarov, Benjamin F. Mann
Summary: The glycans of SARS-CoV-2 spike protein play functional roles in the infection process and are highly conserved. Glycosylation of the receptor-binding domain (RBD) of the spike protein can be controlled and simplified through glycoengineering, affecting its behavior and interaction with host receptors. The antibody S309 can neutralize the impact of different RBD glycoforms on receptor binding affinity.