Analysis for Non-covalent Bonds in Protein Structures Using the DV-Xα Method
DOI:
https://doi.org/10.26877/asset.v8i2.2757Keywords:
computational chemistry, DV-Xα method, non-covalent bond, molecular orbital calculationAbstract
Halogen atoms are increasingly recognized for their ability to form non-covalent halogen bonds in protein–ligand complexesy. To systematically evaluate these interactions, we employed the DV-Xα method to calculate bond overlap populations (BOPs) in protein structures containing halogenated ligands. Using the Protein Data Bank, we identified thousands of entries with fluorine, chlorine, bromine, or iodine atoms. Structural coordinates were extracted around the chlorine atoms of the ligand and subjected to ab initio calculations under multiple truncation schemes. The findings highlight the utility of DV-Xα calculations in characterizing weak interactions and provide insights for future computational drug design employing halogen-containing compounds.
References
[1] M. L. Verteramo et al., “Interplay of halogen bonding and solvation in protein–ligand binding,” iScience, vol. 27, no. 4, p. 109636, Apr. 2024, doi: 10.1016/j.isci.2024.109636.
[2] B. Inscoe, H. Rathnayake, and Y. Mo, “Role of Charge Transfer in Halogen Bonding,” J. Phys. Chem. A, vol. 125, no. 14, pp. 2944–2953, Apr. 2021, doi: 10.1021/acs.jpca.1c01412.
[3] H. M. Berman, “The Protein Data Bank,” Nucleic Acids Research, vol. 28, no. 1, pp. 235–242, Jan. 2000, doi: 10.1093/nar/28.1.235.
[4] R. Sharma, S. Sarkar, S. Chattopadhayay, J. Mondal, and P. Talukdar, “A Halogen‐Bond‐Driven Artificial Chloride‐Selective Channel Constructed from 5‐Iodoisophthalamide‐based Molecules,” Angew Chem Int Ed, vol. 63, no. 19, p. e202319919, May 2024, doi: 10.1002/anie.202319919.
[5] M. G. Walker, C. G. Mendez, A. N. Ho, R. S. Czarny, A. K. Rappé, and P. S. Ho, “Design of a halogen bond catalyzed DNA endonuclease,” Proc. Natl. Acad. Sci. U.S.A., vol. 122, no. 14, p. e2500099122, Apr. 2025, doi: 10.1073/pnas.2500099122.
[6] K. Tsuji et al., “Exploratory Studies of Effective Inhibitors against the SARS-CoV-2 Main Protease by Halogen Incorporation and Amide Bond Replacement,” Chem. Pharm. Bull., vol. 71, no. 12, pp. 879–886, Dec. 2023, doi: 10.1248/cpb.c23-00562.
[7] W. Liu et al., “New Cocrystals of Antipsychotic Drug Aripiprazole: Decreasing the Dissolution through Cocrystallization,” Molecules, vol. 26, no. 9, p. 2414, Apr. 2021, doi: 10.3390/molecules26092414.
[8] J. O’Brien, N. Melnyk, R. S. Lee, M. James, and C. Trujillo, “Computational Design of Bidentate Hypervalent Iodine Catalysts in Halogen Bond‐Mediated Organocatalysis,” ChemPhysChem, vol. 25, no. 22, p. e202400515, Nov. 2024, doi: 10.1002/cphc.202400515.
[9] K. Mu, Z. Zhu, A. Abula, C. Peng, W. Zhu, and Z. Xu, “Halogen Bonds Exist between Noncovalent Ligands and Natural Nucleic Acids,” J. Med. Chem., vol. 65, no. 6, pp. 4424–4435, Mar. 2022, doi: 10.1021/acs.jmedchem.1c01854.
[10] A. Docker, Y. C. Tse, H. M. Tay, A. J. Taylor, Z. Zhang, and P. D. Beer, “Anti‐Hofmeister Anion Selectivity via a Mechanical Bond Effect in Neutral Halogen‐Bonding [2]Rotaxanes,” Angew Chem Int Ed, vol. 61, no. 50, p. e202214523, Dec. 2022, doi: 10.1002/anie.202214523.
[11] N. Gutiérrez-Sánchez, J. Kästner, F. Mendizábal, and S. Miranda-Rojas, “Insights into the Catalytic Mechanism and Selectivity of S -Adenosyl Methionine (SAM)-Dependent Fluorinase toward Carbon–Halogen Bond Formation,” J. Chem. Inf. Model., vol. 65, no. 13, pp. 6998–7012, July 2025, doi: 10.1021/acs.jcim.5c00544.
[12] M. U. Engelhardt et al., “Halogen Bonding on Water─A Drop in the Ocean?,” J. Chem. Theory Comput., vol. 20, no. 23, pp. 10716–10730, Dec. 2024, doi: 10.1021/acs.jctc.4c00834.
[13] J. Sun, D. A. Decato, V. S. Bryantsev, E. A. John, and O. B. Berryman, “The interplay between hydrogen and halogen bonding: substituent effects and their role in the hydrogen bond enhanced halogen bond,” Chem. Sci., vol. 14, no. 33, pp. 8924–8935, 2023, doi: 10.1039/D3SC02348F.
[14] M. H. Daniels et al., “Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9,” J. Med. Chem., vol. 68, no. 9, pp. 9537–9554, May 2025, doi: 10.1021/acs.jmedchem.5c00252.
[15] M. Iwamoto et al., “Bisphenol A derivatives act as novel coactivator-binding inhibitors for estrogen receptor β,” Journal of Biological Chemistry, vol. 297, no. 5, p. 101173, Nov. 2021, doi: 10.1016/j.jbc.2021.101173.
[16] X. Yao, S. Geng, L. Zhu, H. Jiang, and J. Wen, “Environmental pollutants exposure and gestational diabetes mellitus: Evidence from epidemiological and experimental studies,” Chemosphere, vol. 332, p. 138866, Aug. 2023, doi: 10.1016/j.chemosphere.2023.138866.
[17] H. M. Dusza, K. E. Manz, K. D. Pennell, R. Kanda, and J. Legler, “Identification of known and novel nonpolar endocrine disruptors in human amniotic fluid,” Environment International, vol. 158, p. 106904, Jan. 2022, doi: 10.1016/j.envint.2021.106904.
[18] V. Suteau et al., “Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study,” Journal of Hazardous Materials, vol. 479, p. 135619, Nov. 2024, doi: 10.1016/j.jhazmat.2024.135619.
[19] K. Nowak and Ž. Jakopin, “In silico profiling of endocrine-disrupting potential of bisphenol analogues and their halogenated transformation products,” Food and Chemical Toxicology, vol. 173, p. 113623, Mar. 2023, doi: 10.1016/j.fct.2023.113623.
[20] A. R. Kinjo et al., “Protein Data Bank Japan (PDBj): updated user interfaces, resource description framework, analysis tools for large structures,” Nucleic Acids Res, vol. 45, no. D1, pp. D282–D288, Jan. 2017, doi: 10.1093/nar/gkw962.
[21] A. R. Kinjo et al., “New tools and functions in data‐out activities at Protein Data Bank Japan (PDBj),” Protein Science, vol. 27, no. 1, pp. 95–102, Jan. 2018, doi: 10.1002/pro.3273.
[22] G. Bekker et al., “Protein Data Bank Japan: Celebrating our 20th anniversary during a global pandemic as the Asian hub of three dimensional macromolecular structural data,” Protein Science, vol. 31, no. 1, pp. 173–186, Jan. 2022, doi: 10.1002/pro.4211.
[23] Molecular Operating Environment (MOE), 2024.0601 Chemical Computing Group ULC, 910-1010 Sherbrooke St. W., Montreal, QC H3A 2R7, 2025.
[24] H. Adachi, M. Tsukada, and C. Satoko, “Discrete Variational Xα Cluster Calculations. I. Application to Metal Clusters,” J. Phys. Soc. Jpn., vol. 45, no. 3, pp. 875–883, Sept. 1978, doi: 10.1143/JPSJ.45.875.
[25] Delfosse, V., Grimaldi, M., Bourguet, W., 2012, Crystal structure of hERa-LBD (wt) in complex with bisphenol-C, doi: 10.2210/pdb3UUC/pdb
[26] V. Delfosse et al., “Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes,” Proc. Natl. Acad. Sci. U.S.A., vol. 109, no. 37, pp. 14930–14935, Sept. 2012, doi: 10.1073/pnas.1203574109.
[27] T. Masuya, M. Iwamoto, X. Liu, and A. Matsushima, “Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors,” Sci Rep, vol. 9, no. 1, p. 9954, July 2019, doi: 10.1038/s41598-019-46272-y.
[28] S. Alvarez, “A cartography of the van der Waals territories,” Dalton Trans., vol. 42, no. 24, p. 8617, 2013, doi: 10.1039/c3dt50599e.
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