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Nikitin D. Integrated analysis of human retroelement-linked histone modifications for identifying rapidly evolving oncogenic processes PDF📥
ABSTRACT. РHuman retroelements (REs), which comprise approximately 40% of the genome, have played a pivotal role in the evolution of key molecular processes, such as placental development, by introducing novel regulatory elements near host gene promoters and enhancers. Despite their genomic abundance and regulatory influence, the functional trajectories of REs remain poorly understood. Here, leveraging ChIP-seq profiles of histone modifications (H3K4me1, H3K4me3, H3K9ac, H3K27ac, H3K27me3, and H3K9me3) from five human cell lines deposited in the ENCODE database, we systematically ranked the regulatory impact of REs across 25,075 human genes. Gene sets enriched for promoter- and enhancer-associated RE-linked regulatory sites were identified. Consensus gene sets across cell lines were found to be associated with pathways involved in cancer progression, specifically chronic myeloid leukemia and small cell lung cancer, as well as with host defense responses to infection with human T-cell lymphotropic virus type 1. These findings provide new insights into recent human evolution and highlight the ongoing influence of selfish genetic elements on genome regulation and disease susceptibility.
Keywords: retroelements, retrotransposons, genome evolution, chromatin, histone modifications.
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54
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Grabski H. Artifacts caused by crystallographic neighbors during docking. the importance of the biological unit for evaluating docking accuracy PDF📥
ABSTRACT. Reliable structure-based virtual screening critically depends on the accuracy of experimental protein–ligand complexes. However, many crystallographic models in the Protein Data Bank (PDB) contain crystalpacking neighbors that distort the local geometry of binding sites. In this work, the impact of crystallographic neighbors on molecular docking accuracy using Molsoft ICM-Pro was systematically assessed. All ligands were docked starting from two-dimensional structures, without prior conformational information, to mimic realistic virtual screening conditions. Across three representative systems Schistosoma mansoni SmBRD3(2), human TIM-3, and USP5 ZnF-UBD that crystal neighbors can have a huge impact was observed. Incorporating neighboring molecules yielded dramatic improvements, reducing RMSD values
below 2 Å and substantially enhancing docking and RTCNN scores. The results emphasize the necessity of careful analysis of crystallographic structures before docking to ensure correct biological unit, reproducibility, reliability, and meaningful interpretation of computational screening outcomes.
Keywords: Virtual screening, Crystallographic neighbors, Molecular docking, Protein–ligand interactions, Structure-based drug discovery.
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70
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Grabska S. Effect of EGFR conformational plasticity on the accuracy of covalent EGFR inhibitor docking: an improved approach PDF📥
ABSTRACT. Selecting the appropriate crystallographic conformation of a target protein is essential for reliable structure-based virtual screening. In this study, conformational variability of the epidermal growth factor receptor (EGFR) was investigated and how it influences docking accuracy of Afatinib, a dual covalent inhibitor of EGFR, and HER2. Using five EGFR crystal structures (4G5J, 4I22, 3W33, 3POZ, and 5U8L), self- and crossdocking analyses were performed in ICM-Pro to assess binding precision, pose stability, and scoring performance. Self-docking of Afatinib into its native complex (4G5J) reproduced the experimental pose with an RMSD of 0.95 Å, validating the protocol. Among alternative conformations, 4I22 yielded the closest structural agreement, demonstrating an RMSD of 1.02 Å and superior docking scores, while other structures showed substantial deviations in key active-site residues, resulting in distorted poses and lower binding scores. These findings reveal that subtle rearrangements of residues surrounding Cys797, Met793, and Lys745 critically affect ligand accommodation and covalent bond formation. The results emphasize that protein conformational selection, particularly from high-resolution structures - profoundly influences docking fidelity. Incorporating multiple conformations through cross- docking enhances predictive robustness and better reflects the dynamic nature of protein–ligand recognition in virtual screening workflows.
Keywords: EGFR, afatinib, covalent inhibitor, cross-docking, protein conformation.
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