(PSSJ2022 oral) Inverse Mixed-Solvent Molecular Dynamics for Visualization of Residue Interaction Profile of Molecular Probes（第22回 日本蛋白質科学会年会）

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1. 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa 1 Inverse Mixed-Solvent Molecular Dynamics for Visualization of Residue Interaction Profile of Molecular Probes (インバース共溶媒分子動力学法による分子プローブ周辺残基環境の可視化) 〇Keisuke Yanagisawa1, Ryunosuke Yoshino2, Genki Kudo2, Takatsugu Hirokawa2 1 Tokyo Tech. / 2 Univ. Tsukuba K Yanagisawa, R Yoshino, G Kudo, and T Hirokawa. Int. J. Mol. Sci. 23, 4749, 2022. doi: 10.3390/ijms23094749 N N O O - Inverse MSMD OH Mixed-solvent MD (MSMD) O7-12
2. Outline 2 • Introduction • An Overview of Inverse MSMD protocol • Application examples • Benzamidine • Catechol • Benzene • Conclusion 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa
3. Structure-Based Drug Design (SBDD) 3 Design a drug compound with a protein structure Introduction 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa Search/Modify a chemical structure fitted to it better O N O N O O N N N O N O O O O O O IC50 ≈ 5nM IC50 = 0.9nM
4. Interaction profiles of functional groups 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa 4 It has been explored based on known 3D co-structures Applicable only for well-known chemical substructures Kasahara+2013[1] Wang+2011[2] [1] Kasahara K et al., JCIM 53, 241-248, 2013. [2] Wang L et al., JCIM 51, 807-815, 2011. Introduction Profiles of: - Presence of residues - Spatial placement
5. Mixed-solvent MD (MSMD) simulation 5 Introduction 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa MD in explicit water mixed with probe molecules Explore a protein surface where probe is likely to bind N N N OH N N Probes High probability regions MSMD simulation Possible to enumerate interaction poses of any probes [1] Yanagisawa K et al., JCIM 61, 2744-2753, 2021.
6. Research aim & achievement 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa 6 Aim: Explore interaction profiles of any probes ✓ Independent from known co-structures Achievement：Propose Inverse MSMD method ✓ Extract interaction poses from MSMD ✓ Visualize with mesh representation Introduction *Code is available at https://github.com/keisuke-yanagisawa/exprorer_msmd Interaction poses obtained from MSMD simulation
7. The proposed method 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa 7 Results & Discussion Enumerate preferred protein surfaces Enumerate interaction poses Aggregate to a interaction profile MSMD with 15 diverse proteins
8. Benzamidine: Assessment of the method 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa 8 Benzamidine has a positive-charged (amidino) group Acidic amino acid residues localized against it The result agreed with X-ray structures Results & Discussion Interaction profile Superimposition to a 3D structure (Trypsin + Benzamidine) Ser171 Asp170 red: acidic blue: basic cyan: hydrophilic green: hydrophobic
9. Catechol: Preference of hydroxy groups 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa 9 Catechol has two hydroxy groups Interestingly, acidic residues localized against them rather than hydrophilic residues Results & Discussion Interaction profile Superimposition to a 3D structure (Catalase + Catechol) red: acidic blue: basic cyan: hydrophilic green: hydrophobic Leu150 Asp110 Leu181
10. Benzene: Weak binder 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa 10 Benzene does not show any strong preference The profile indicates the importance of chemical context Merely focusing on phenyl group is not enough Results & Discussion Interaction profile red: acidic blue: basic cyan: hydrophilic green: hydrophobic
11. Conclusion & Future work 8th June, 2022 PSSJ2022 | O7-12 | K Yanagisawa 11 Conclusion ・Propose Inverse MSMD to explore interactions ・The method can be applied to any probes Future work ・Quantitative evaluation of consistency ・Application to more diverse probes Conclusion