Coarse-grained molecular dynamics provides a means for simulating the assembly and interactions of macromolecular complexes at a reduced level of representation, thereby allowing both longer timescale and larger sized simulations. Here, we describe an enhanced fragment-based protocol for converting macromolecular complexes from coarse-grained to atomistic resolution, for further refinement and analysis. While the focus is upon systems that comprise an integral membrane protein embedded in a phospholipid bilayer, the technique is also suitable for membrane-anchored and soluble protein/nucleotide complexes. Overall, this provides a method for generating an accurate and well-equilibrated atomic-level description of a macromolecular complex. The approach is evaluated using a diverse test set of 11 system configurations of varying size and complexity. Simulations are assessed in terms of protein stereochemistry, conformational drift, lipid/protein interactions, and lipid dynamics.
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http://dx.doi.org/10.1021/acs.jctc.1c00295 | DOI Listing |
Int J Mol Sci
November 2024
Center for Research and Education in Nanobioengineering, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
The complexities inherent in drug development are multi-faceted and often hamper accuracy, speed and efficiency, thereby limiting success. This review explores how recent developments in machine learning (ML) are significantly impacting target-based drug discovery, particularly in small-molecule approaches. The Simplified Molecular Input Line Entry System (SMILES), which translates a chemical compound's three-dimensional structure into a string of symbols, is now widely used in drug design, mining, and repurposing.
View Article and Find Full Text PDFToxics
November 2024
Department of Bio-AI Convergence, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea.
It is imperative to comprehend the mechanisms that underlie drug toxicity in order to enhance the efficacy and safety of novel therapeutic agents. The capacity to identify molecular pathways that contribute to drug-induced toxicity has been significantly enhanced by recent developments in omics technologies, such as transcriptomics, proteomics, and metabolomics. This has enabled the early identification of potential adverse effects.
View Article and Find Full Text PDFCurr Issues Mol Biol
November 2024
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
The pathogen of COVID-19, SARS-CoV-2, has caused a severe global health crisis. So far, while COVID-19 has been suppressed, the continuous evolution of SARS-CoV-2 variants has reduced the effectiveness of vaccines such as mRNA-1273 and drugs such as Remdesivir. To uphold the effectiveness of vaccines and drugs prior to potential coronavirus outbreaks, it is necessary to explore the underlying mechanisms between biomolecules and nanodrugs.
View Article and Find Full Text PDFPhys Chem Chem Phys
December 2024
Department of Chemistry and Biochemistry, The University of Texas at Dallas, 800 West Campbell Road, Richardson, Texas 75080, USA.
Developing the multipolar-polarizable AMOEBA force field for large molecules presents its own set of complexities. However, by segmenting the molecules into smaller fragments and ensuring that each fragment is transferable to other systems, the process of parameterizing large molecules such as fatty acids can be simplified without compromising accuracy. In this study, we present a fragment-based AMOEBA FF development for long-chain fatty acid ionic liquids (LCFA-ILs).
View Article and Find Full Text PDFChem Sci
November 2024
College of Pharmaceutical Sciences, Zhejiang University Hangzhou 310058 Zhejiang China
3D structure-based molecular generation is a successful application of generative AI in drug discovery. Most earlier models follow an atom-wise paradigm, generating molecules with good docking scores but poor molecular properties (like synthesizability and drugability). In contrast, fragment-wise generation offers a promising alternative by assembling chemically viable fragments.
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