Review
Chemistry, Medicinal
Sergio Algar, Mercedes Martin-Martinez, Rosario Gonzalez-Muniz
Summary: Researchers have developed a variety of non-peptide alpha-helix mimetics to modulate protein-protein interactions, with the potential to stabilize or disrupt therapeutically relevant PPIs. The diverse chemical structures and substituents allow for a wide range of choices in research, offering new opportunities for future studies on protein interactions.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Junyang Liu, Shoubin Tang, Jia-Lei Yan, Tao Ye
Summary: A novel hydrogen bond surrogate-based alpha-helix mimetic was designed using covalent H-bond replacement and an ether linkage to substitute an amide bond. CD studies showed that the mimetic maintained stable conformations in aqueous buffer at high temperatures.
Article
Biochemistry & Molecular Biology
Jingtan Su, Rucha Arun Bapat, Gayathri Visakan, Janet Moradian-Oldak
Summary: By analyzing Ambn sequences of 53 species, we found that a potential amphipathic helix (AH) within the sequence encoded by Exon 5 of Ambn appeared in species with prismatic enamel. Synthetic peptides derived from mammalian Ambn interacted with liposomes and caused liposome leakage, while peptides from species without prismatic enamel did not show similar effects. Our findings suggest that the AH motif is closely related to the emergence of enamel prismatic structure and is involved in Ambn's regulation of cell morphology and polarization genes.
MOLECULAR BIOLOGY AND EVOLUTION
(2022)
Article
Chemistry, Multidisciplinary
Keisuke Ikeda, Ayame Horiuchi, Misa Yoshino, Chinatsu Shimizu, Hiroyuki Nakao, Minoru Nakano
Summary: Specific phospholipids can promote the formation of stable nanofibers with 18A[A11C], with the acyl chain length of phosphatidylcholines influencing the structural stability of the nanofibers. Molecular interactions between peptides and phospholipid headgroups and acyl chains are responsible for nanofiber formation, which can be reversibly controlled by temperature and concentration. These findings shed light on the design of nanoassembling structures.
Article
Biochemistry & Molecular Biology
Kazuma Shimanaka, Bryan Shi, Lisa Brontesi, Heba Alnakhala, Vidyashree Jayanthi, Kanagaraj Subramanian, Nagendran Ramalingam, Arati Tripathi, Ulf Dettmer
Summary: This study reveals the significance of amino acid composition in alpha-synuclein for its interaction with cellular membranes and phosphorylation, providing insights into the biology of alpha-synuclein in health and disease.
Article
Chemistry, Medicinal
Shelby R. Kell, Zhen Wang, Haitao Ji
Summary: The study reveals a convergence of binding conformations of alpha-helical hydrophobic hot spots in protein-protein complex structures, regardless of the position along the helix. This observation streamlines the development of pharmacophore models and may be useful for the design of novel alpha-helical hot spot mimetics.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Albert Escobedo, Jonathan Piccirillo, Juan Aranda, Tammo Diercks, Borja Mateos, Carla Garcia-Cabau, Macarena Sanchez-Navarro, Busra Topal, Mateusz Biesaga, Lasse Staby, Birthe B. Kragelund, Jesus Garcia, Oscar Millet, Modesto Orozco, Murray Coles, Ramon Crehuet, Xavier Salvatella
Summary: This study presents design rules for creating peptides that fold into single alpha-helices by utilizing glutamine side chain to main chain hydrogen bonds. These peptides can be used to target globular proteins and have a wide range of applications.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Lydia I. Dewis, Madhavachary Rudrakshula, Christopher Williams, Elisabetta Chiarparin, Eddie L. Myers, Craig P. Butts, Varinder K. Aggarwal
Summary: Using α-helix mimetics as inhibitors of protein-protein interactions is a prevalent therapeutic strategy. Controlling the conformation of mimetics through destabilizing syn-pentane interactions can enhance their efficacy.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Virology
Ken Komatsu, Nobumitsu Sasaki, Tetsuya Yoshida, Katsuhiro Suzuki, Yuki Masujima, Masayoshi Hashimoto, Satoru Watanabe, Naoya Tochio, Takanori Kigawa, Yasuyuki Yamaji, Kenro Oshima, Shigetou Namba, Richard S. Nelson, Tsutomu Arie
Summary: In this study, it was found that an amphipathic alpha-helix structure downstream from the methyltransferase core domain of PlAMV replicase is crucial for membrane association and virus replication. The conserved proline-kinked helical sequence among potexviruses plays a key role in forming a perinuclear complex during virus infection. However, the formation of this complex by the replicase alone does not necessarily indicate successful virus replication.
JOURNAL OF VIROLOGY
(2021)
Article
Biochemistry & Molecular Biology
Mohammed Hakmi, E. L. Mehdi Bouricha, Jihane Akachar, Badreddine Lmimouni, Jaouad El Harti, Lahcen Belyamani, Azeddine Ibrahimi
Summary: The rapid spread and increasing number of cases of the novel coronavirus requires immediate development of effective therapies, vaccines, and accurate diagnosis tools. This study used computational simulations to explore small-molecule inhibitors that could disrupt the virus's entry into host cells. Critical target regions were identified and promising candidates with favorable binding affinities were found.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Chemistry, Inorganic & Nuclear
Jeyson Esquivel Curichimba, Roberto Luiz Andrade Haiduke
Summary: In this study, the reaction mechanism of the semi-hydrogenation reaction catalyzed by {(C5H4N)(C6H4)}RuCl(CO)(PPh3)(2) catalyst was evaluated using Density Functional Theory. The calculations revealed the existence of four new intermediates to overcome steric hindrance issues and explained the release of the products. Additionally, the turnover frequency (TOF)-determining transition state (TDTS) and intermediate (TDI) were identified in the first cycle using the energetic span model.
EUROPEAN JOURNAL OF INORGANIC CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Hani A. Alhadrami, Ahmed M. Sayed, Hossam M. Hassan, Mostafa E. Rateb, Karim Abdelkader
Summary: This study presents a safe and effective approach utilizing cecropin A to facilitate hen egg white lysozyme access to peptidoglycan layers. The combination of HEWL and cecropin A shows potential antibacterial activity against Salmonella enterica.
Editorial Material
Cell Biology
Taki Nishimura, Gianmarco Lazzeri, Sharon A. Tooze, Roberto Covino
Summary: In our study, we have discovered that ATG3 exhibits dynamic structural changes on autophagic membranes, allowing for efficient LC3 lipidation. The presence of an amphipathic alpha-helix with bulky and hydrophobic residues enables transient membrane association and facilitates enzymatic reaction of ATG3. This research provides insights into the understanding of how ATG proteins interact with membranes during autophagosome formation.
Article
Biochemistry & Molecular Biology
Calvin Yeager, Griffin Carter, David W. Gohara, Neela H. Yennawar, Eric J. Enemark, Jamie J. Arnold, Craig E. Cameron
Summary: This study elucidates the first biochemical mechanism of the enteroviral 2C protein and confirms its applicability to other members of the enterovirus genus. The research shows that RNA binds to the 2C protein driven by the backbone, stimulating ATPase activity. This provides an important biochemical description of the determinants driving specificity and catalytic efficiency of the picornaviral 2C ATPase.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Qianshen Zhang, Zhiyan Wen, Xin Zhang, Jiajie She, Xiaoling Wang, Zongyu Gao, Ruiqi Wang, Xiaofei Zhao, Zhen Su, Zhen Li, Dawei Li, Xiaofeng Wang, Yongliang Zhang
Summary: The study employed TurboID-based proximity labeling to investigate the replication of a plant virus and identified RETICULON-LIKE PROTEIN B2 as a proviral factor in viral replication complex formation.
Review
Chemistry, Analytical
Pieter De Gauquier, Kenno Vanommeslaeghe, Yvan Vander Heyden, Debby Mangelings
Summary: This article presents an overview of molecular modelling approaches for chiral separations on polysaccharide-based and macrocyclic antibiotic chiral selectors. Both atomistic calculations and empirical fitting procedures are discussed. Atomistic calculations, such as docking and molecular dynamics, can provide insights into the chiral recognition mechanism by modeling the interactions between enantiomers and the chiral stationary phase. On the other hand, empirical fitting procedures involve mathematical models that are fitted to experimental observations using theoretical molecular descriptors. These models can be used to predict a specific response, such as retention, in chiral separations. The article also discusses different regression models, such as multiple linear regression and partial least squares.
ANALYTICA CHIMICA ACTA
(2022)
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)
Article
Chemistry, Physical
Cheol Jeong, Ryan Franklin, Karen J. Edler, Kenno Vanommeslaeghe, Susan Krueger, Joseph E. Curtis
Summary: Lipid nanodiscs are promising reagents to solubilize membrane proteins in nativelike environments and characterize them. Small-angle neutron scattering can determine the low-resolution structures of proteins, and contrast variation methods can enhance this process. It is possible to eliminate the scattering of the nanodisc by tuning the neutron scattering length densities.
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
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)
