Article
Chemistry, Medicinal
Marine Bugnon, Mathilde Goullieux, Ute F. Rohrig, Marta A. S. Perez, Antoine Daina, Olivier Michielin, Vincent Zoete
Summary: Computer-aided drug design tools play a crucial role in supporting and accelerating the steps of drug discovery, with structure-based approaches using the three-dimensional structure of the targeted biomacromolecule as a major source of information. Generating parameters for small molecules remains challenging due to the large number of existing chemical groups. The updated version of SwissParam provides various new features, including the ability to set up covalent ligands and import molecules from different file formats or via a molecular sketcher.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
M. Lundborg, J. Lidmar, B. Hess
Summary: The accelerated weight histogram method is an enhanced sampling technique that efficiently explores free energy landscapes and can be used for sampling alchemical transformations, easy to use and can be combined with other reaction coordinates.
JOURNAL OF CHEMICAL PHYSICS
(2021)
Article
Biochemistry & Molecular Biology
Woo-jin Jeong, Jiyoon Bu, Philip Mickel, Yanxiao Han, Piper A. Rawding, Jianxin Wang, Hanbit Kang, Heejoo Hong, Petr Kral, Seungpyo Hong
Summary: Avidity-based SARS-CoV-2 antagonist, developed using dendrimer-peptide conjugates (DPCs), shows effective COVID-19 treatment by effectively blocking the interaction between ACE2 and SARS-CoV-2. The larger DPCs exhibit significantly enhanced binding strength compared to free peptides, and molecular dynamics simulation reveals how dendrimer-mediated multivalent binding enhances SARS-CoV-2 blockade.
Article
Chemistry, Medicinal
Marcelo D. Poleto, Justin A. Lemkul
Summary: G-quadruplexes (GQs) are noncanonical nucleic acid structures formed by guanine-rich sequences in DNA and RNA. They play crucial roles in gene regulation and maintenance. This study used various simulation techniques to investigate the impact of ion binding on GQ dynamics and revealed subtle differences between DNA and RNA GQs.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Jung Cho, Yifeng Yun, Hongyi Xu, Junliang Sun, Allen W. Burton, Karl G. Strohmaier, Gene Terefenko, Hilda Vroman, Mobae Afeworki, Guang Cao, Hao Wang, Xiaodong Zou, Tom Willhammar
Summary: The structure of novel medium-pore borosilicate zeolite EMM-25 was determined using continuous rotation electron diffraction (cRED). A new ammonium dication OSDA was found to reduce synthesis time significantly, and structural disorder in the form of swinging zigzag chains was observed in the EMM-25 framework.
CHEMISTRY OF MATERIALS
(2021)
Article
Biochemistry & Molecular Biology
Monsurat Motunrayo Lawal, Valerie Vaissier Welborn
Summary: Electrostatic preorganization, structural and dynamic heterogeneity are commonly used to explain enzyme catalysis. However, they are often considered incompatible due to the rigidity required for permanent electrostatic effects. In this study, electric fields are used to analyze enzymatic catalysis, revealing that the residues contributing the most to electrostatic interactions in the active site of Adenylate Kinase are also the most flexible. Furthermore, entropy-tuning mutations increase flexibility at the picosecond timescale, allowing for a wider range of conformations within shorter time periods.
Article
Chemistry, Physical
Shiji Zhao, Haixin Wei, Piotr Cieplak, Yong Duan, Ray Luo
Summary: This study evaluates the accuracy of polarizable Gaussian Multipole (pGM) models in reproducing quantum mechanical interaction energies, many-body interaction energies, and their contributions. The results show that pGM models outperform other force fields and have the potential to serve as templates for developing next-generation polarizable force fields.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Multidisciplinary Sciences
Robin A. Corey, Wanling Song, Anna L. Duncan, T. Bertie Ansell, Mark S. P. Sansom, Phillip J. Stansfeld
Summary: The study reveals that bacterial membrane proteins bind to specific lipids, especially cardiolipin, and shows an asymmetry in lipid binding between membrane leaflets. Through molecular dynamics simulations, over 700 independent cardiolipin binding sites were identified, defining a molecular basis for high-affinity cardiolipin binding sites on bacterial membrane proteins.
Article
Computer Science, Interdisciplinary Applications
Dong An, Lin Lin, Michael Lindsey
Summary: The XLMD method is a useful framework for reducing the computational cost of molecular dynamics simulations with constrained latent variables. This study provides the first error analysis of the XLMD method in the context of a classical polarizable force field model, showing that the method converges with small errors when the latent variables' initial values are compatible.
JOURNAL OF COMPUTATIONAL PHYSICS
(2022)
Article
Biochemistry & Molecular Biology
Harsh Bhatia, Fikret Aydin, Timothy S. Carpenter, Felice C. Lightstone, Peer-Timo Bremer, Helgi I. Ingolfsson, Dwight V. Nissley, Frederick H. Streitz
Summary: Multiscale modeling in structural biology has a long history and aims to overcome the limitations of atomistic molecular dynamics in terms of time and length scales. Modern machine learning techniques, particularly deep learning, have revolutionized various scientific and engineering fields, including multiscale modeling. Deep learning has been successful in distilling information from fine-scale models and defining latent spaces for efficient exploration of conformational space. The integration of machine learning, multiscale simulation, and high-performance computing holds great promise for discovery and innovation in structural biology.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
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, Multidisciplinary
Mert Y. Sengul, Alexander D. MacKerell
Summary: Metal ions, particularly Mg2+, play a role in stabilizing RNA's tertiary structures. However, the atomic-level mechanisms underlying this process are not fully understood. In this study, computational techniques were combined to investigate the specific interactions between Mg2+ ions and RNA, particularly in the pseudoknot structure of the Twister ribozyme.
Article
Engineering, Environmental
Yunfeng Mao, Tianhang Zhou, Longqian Xu, Weidong Wu, Rong Wang, Zhibo Xiong, Deli Wu, Huancong Shi
Summary: This study investigated the structural and dynamic properties of hydrated ions in a 3-nm nanopore of a CDI electrode using molecular dynamics simulation. The results showed that the polarization models and nonpolarizable models had some differences in the dielectric constants in the nanopore, which were influenced by the rotational dynamics of water molecules and hydrogen bonding. In addition, the dielectric constant played a crucial role in ion transport in the electrode. This research provides fundamental theories and implications for the theoretical analysis of ion electrosorption in a CDI electrode and can enhance its application in water treatment.
CHEMICAL ENGINEERING JOURNAL
(2022)
Article
Chemistry, Medicinal
Bas van Beek, Juliette Zito, Lucas Visscher, Ivan Infante
Summary: In this work, a Compound Attachment Tool (CAT) is presented for the automatic construction of composite chemical compounds. CAT supports the functionalization of organic, inorganic, and hybrid organic-inorganic materials. The CAT workflow involves defining anchoring sites, optimizing ligand structures, and storing the resulting superstructures in various formats.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Physical
Moritz Thuerlemann, Lennard Boselt, Sereina Riniker
Summary: Simulations of biological molecular systems using electronic structure methods are difficult, so empirical methods such as force fields (FF) are commonly used. Parameterizing FF is time-consuming and traditionally relies on experimental data, but recent efforts have explored automatization and machine-learning based potentials. This study proposes an alternative strategy that combines machine learning and gradient-descent optimization while retaining a physics-based functional form, enabling efficient simulations with interpretability and robustness. The proposed method successfully assigned atom types and FF parameters for various systems and properties based on element information, molecular topology, and reference potential energies.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Multidisciplinary Sciences
Nousheen Parvaiz, Faisal Ahmad, Wenbo Yu, Alexander D. MacKerell, Syed Sikander Azam
Summary: This study explores the use of combination therapy to identify novel beta-lactamase inhibitors that can inactivate the enzyme of pathogens, providing a new approach in combating multi-drug resistant pathogens. By utilizing computational screening and experimental validation, potential compounds were identified with beta-lactamase inhibition and antibacterial activity against MDR clinical isolates. These non-beta-lactam-based inhibitors have the potential to be used in combination therapy with beta-lactam antibiotics against resistant strains.
Article
Chemistry, Physical
Anmol Kumar, Poonam Pandey, Payal Chatterjee, Alexander D. Jr Jr MacKerell
Summary: The Drude polarizable force field captures electronic polarization effects and is useful for simulating biomolecules and other molecules. Deep neural network models can accurately predict molecular dipole moments and polarizabilities.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Multidisciplinary
Abhishek A. Kognole, Jumin Lee, Sang-Jun Park, Sunhwan Jo, Payal Chatterjee, Justin A. Lemkul, Jing Huang, Alexander D. MacKerell, Wonpil Im
Summary: The Drude Prepper tool has been developed in CHARMM-GUI to facilitate the use of polarizable FF based on the classic Drude oscillator model. It allows for easy construction of Drude FF-based PSF and generation of input for MD simulations using various simulation packages. The stability and effectiveness of the Drude Prepper protocol and inputs have been demonstrated through validation with a variety of heterogeneous systems.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Adam T. Green, Amanda J. Pickard, Rongzhong Li, Alexander D. MacKerell, Ulrich Bierbach, Samuel S. Cho
Summary: This study uses circular dichroism spectroscopy to show the parallel topologies of two putative ribosomal G-quadruplex sequences, and validates and refines the modeled structures using molecular dynamics simulations. The results provide a structural foundation for understanding G-quadruplex functions and designing novel chemotherapeutics.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Review
Chemistry, Multidisciplinary
Himanshu Goel, Anthony Hazel, Wenbo Yu, Sunhwan Jo, Alexander D. MacKerell
Summary: SILCS utilizes molecular simulation to obtain functional group affinity patterns for drug discovery, allowing for identification of novel ligand binding pockets, prediction of protein-ligand binding affinities, and other applications in computer-aided drug design. It represents a comprehensive approach to improve drug development processes through accuracy and throughput enhancements.
NEW JOURNAL OF CHEMISTRY
(2022)
Article
Chemistry, Physical
Payal Chatterjee, Mert Y. Sengul, Anmol Kumar, Alexander D. MacKerell
Summary: The outcomes of computational chemistry and biology research are greatly influenced by the choice of forcefield used in molecular simulations. This study develops a deep learning-based framework for optimizing van der Waals interactions in molecular simulations. The resulting LJ parameters (interactions between atoms) are validated for their performance in reproducing condensed phase thermodynamic properties and demonstrate improved accuracy in reproducing solvent and crystal properties.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Medicinal
Asuka A. Orr, Suliman Sharif, Junmei Wang, Alexander D. MacKerell
Summary: Generalized force fields (FFs) are extensions of biomolecular FFs used for organic molecules. However, their application to arbitrary molecules requires caution to ensure their integrity.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Physical
Abhishek A. Kognole, Anthony Hazel, Alexander D. MacKerell
Summary: RNA molecules can be potential drug targets in various diseases due to their dysregulated expression or misfolding. Noncoding RNAs, which account for a large part of the human genome, have complex structures and can be targeted by small molecules. The SILCS computational approach, termed SILCS-RNA, was extended to target RNA in this study and evaluated against seven RNA targets. The method provides detailed functional group affinity patterns and facilitates the identification of new potential binding sites and ligand design.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Physical
Wenbo Yu, David J. Weber, Alexander D. MacKerell
Summary: Covalent drug design plays a significant role in drug discovery by forming a covalent bond with targeted residues, leading to a more effective therapeutic approach. Computational methods can identify reactive residues, test potential reactivities, and predict noncovalent contributions to binding. SILCS, a functional group mapping approach, considers protein flexibility, functional group, and protein desolvation along with functional group-protein interactions. SILCS-Covalent, an integrated workflow, can qualitatively and quantitatively inform covalent drug discovery.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Yalun Yu, Richard M. Venable, Jonathan Thirman, Payal Chatterjee, Anmol Kumar, Richard W. Pastor, Benoit Roux, Alexander D. MacKerell Jr, Jeffery B. Klauda
Summary: Accurate empirical force fields of lipid molecules are crucial for molecular dynamics simulations of various lipid systems and heterogeneous systems. The polarizable Drude force field has been optimized in this study to improve its accuracy in simulating pure bilayers and membranes. By using both experimental and quantum mechanical data, the optimized force field shows good agreement with a range of experimental observables. The polarizable Drude2023 force field is anticipated to advance our understanding of electronic polarization in lipid systems.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Multidisciplinary
Mingtian Zhao, Abhishek A. Kognole, Sunhwan Jo, Aoxiang Tao, Anthony Hazel, Alexander D. MacKerell Jr
Summary: In this study, the sampling efficiency of the GCMC method was improved by applying known cavity-bias and configurational-bias algorithms on GPU architecture. The method was parallelized using CUDA and OpenCL, resulting in simultaneous sampling of a large number of configurations during insertion attempts. The partitioning scheme allowed for simultaneous insertion attempts for large systems, significantly improving efficiency. The algorithm was shown to be useful in the application of the site-identification by ligand competitive saturation (SILCS) co-solvent sampling approach for the protein CDK2.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Asuka A. Orr, Aoxiang Tao, Olgun Guvench, Alexander D. MacKerell
Summary: Protein-based therapeutics often face challenges of protein aggregation and high solution viscosity due to high concentrations of active protein. The charge of a protein, affected by its environment, plays a significant role in these solution behaviors. This study presents a structure-based approach called SILCS-Biologics, which predicts the effective charge of proteins by considering the competition between ions and the presence of buffers.
MOLECULAR PHARMACEUTICS
(2023)
Article
Chemistry, Multidisciplinary
Mert Y. Sengul, Alexander D. MacKerell
Summary: Metal ions, particularly Mg2+, play a role in stabilizing RNA's tertiary structures. However, the atomic-level mechanisms underlying this process are not fully understood. In this study, computational techniques were combined to investigate the specific interactions between Mg2+ ions and RNA, particularly in the pseudoknot structure of the Twister ribozyme.
Article
Chemistry, Multidisciplinary
Himanshu Goel, Wenbo Yu, Alexander D. MacKerell
Summary: This article presents the application of structure- and ligand-based approaches in simulating and predicting hERG drug liability. By combining the SILCS method with physicochemical properties, predictive models for hERG blockade were developed, resulting in improved predictability and aiding in rational drug design to minimize hERG risk.
CHEMISTRY-SWITZERLAND
(2022)
Article
Chemistry, Multidisciplinary
Mert Y. Sengul, Alexander D. MacKerell
Summary: The presence of polarizability in the force field improves the stability of RNA hairpin structures and leads to variations in dipole moments and ion distribution. Molecular dynamics simulations play a crucial role in modeling biomolecular systems, and the treatment of electrostatic interactions in the force field strongly affects simulation accuracy. In this study, the impact of polarization on structural properties, dipole moment distributions, and cation interactions in RNA hairpin systems is investigated using polarizable and non-polarizable nucleic acid force fields.
JOURNAL OF COMPUTATIONAL BIOPHYSICS AND CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Michal Novotny, Matus Dubecky, Frantisek Karlicky
Summary: This paper investigates the accuracy of different DFT-based computational approaches in calculating the equilibrium lattice constants and exfoliation energy of hexagonal boron nitride (h-BN). The results are compared with experiments and reference QMC calculations to evaluate the accuracy of these computational methods.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2024)
Article
Chemistry, Multidisciplinary
Luigi Crisci, Federico Coppola, Alessio Petrone, Nadia Rega
Summary: The charge transfer dynamics in asymmetrically substituted indenotetracene molecules upon photo-excitation were investigated using real-time time-dependent density functional theory simulations. The study found that the electron-donating character of the substituents affects the overall electronic energy spacing and ultrafast charge transfer dynamics.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2024)
Article
Chemistry, Multidisciplinary
Vasilii Korotenko, Hendrik Zipse
Summary: The stability of various radicals and molecules has been studied using different theoretical methods, and good correlations between theoretical calculations and experimental results have been found. The effects of hydrogen bonding interactions on the stability of oxygen-centered radicals have also been investigated.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2024)
Article
Chemistry, Multidisciplinary
Oleg Egorov, Michael Rey, Dominika Viglaska, Andrei V. Nikitin
Summary: In this work, the rovibrational energy levels of four isotopologues of methylene were calculated using a new accurate ab initio potential energy surface. The accuracy of the calculations was improved by considering scalar relativistic effects, DBOC, and high-order electronic correlations. For the first time, all available experimental rovibrational transitions were reproduced with high accuracy, without any empirical corrections.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2024)