(CBI2025) Quantitative Estimation of Protein-Ligand Substructure Interaction with Inverse Mixed-Solvent Molecular Dynamics Simulation

Inverse MSMD 法によるタンパク質－リガンド部分構造 相互作用 定量的評価手法の開発

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1. 1. 東京科学⼤・情報理⼯・情⼯ | Comput. Sci., Sch. Comput., Science Tokyo 2. 筑波⼤・医学医療 | Faculty Med., Univ. Tsukuba 3. 筑波⼤・トランスボーダー | TMRC, Univ. Tsukuba 4. 筑波⼤・理情⽣・数物 | Appl. Sci., Grad. Sch. Sci. Tech., Univ. Tsukuba Inverse MSMD 法によるタンパク質－リガンド部分構造 相互作用 定量的評価⼿法の開発 This work was partly supported by JSPS KAKENHI (23K24939, 23K28185, 25K03215), Kayamori Foundation of Informational Science and Advancement, and AMED BINDS (JP25ama121026, JP25ama121029). Acknowledgements [1] Yanagisawa, K., Yoshino, R., Kudo, G., Hirokawa, T. IJMS 23: 4749, 2022. [2] Soga, S., et al. JCIM 47: 2287-2292, 2007. [3] Friberg, A., et al. JMC 56: 15-30, 2013. [4] Liang, J., et al., Eur J Med Chem 67, 175-187, 2013. [5] Chessari, G., et al. JMC 58: 6574-6588, 2015. References 柳澤 渓甫 | Keisuke Yanagisawa1 ◦ 吉野 龍ノ介 | Ryunosuke Yoshino2,3 ⼯藤 玄己 | Genki Kudo4 広川 貴次 | Takatsugu Hirokawa2,3 Inverse mixed-solvent molecular dynamics (Inverse MSMD) estimates residue interaction profile of a ligand substructure. In this study, we propose a matching score between a protein and a profile. The score shows r = 0.45-0.50 for SAR data. We also shows the robustness to side-chain flexibility. Abstract https://github.com/keisuke-yanagisawa/exprorer_msmd source code: MSMD protocol MD engine GROMACS 2019.4 Force field Amber ff14SB (protein) GAFF2 (probes) Water model TIP3P Pseudo repulsion between probes LJ (σ = 2nm, ε = 1 10-6 kcal) between centers of probes Conc. of probes ≈ 0.25M Time step 2 fs Production run 800 ns (40 ns 20 runs) per a probe Trajectory Snapshots every 10 ps, in 20-40 ns MSMD simulations with 15 diverse proteins were conducted per probe. Inverse MSMD (mixed-solvent molecular dynamics) Method: Profile-Structure Matching Results Mixed-solvent MD (MSMD) MD in explicit water mixed with probe molecules Applications: Hotspot detection, Binding affinity prediction MSMD simulation Probe existence probability Probes Probe poses in MSMD snapshots Extract & aggregate Cβ atom positions Interaction profile (19 amino acids w/o Gly) Inverse MSMD [1] Estimating interaction profile of probes via MSMD Interaction profile: spatial Cβ atom existence probability Obtaining protein-independent interaction information MSMD simulation for a protein of interest is always required The profile might be applied analyses w/o additional MSMD Result 1: Binding affinity prediction with two SAR data Result 2: Robustness of our method (XIAP [5]) Our method is robust to side chain-level flexibility Initial complex (PDBID: 5C7A) N Cl Crashed to Lys substitution point score = 29.79 (exp. IC 𝟎. 𝟔𝟒 μM) score = 37.86 (exp. IC 𝟎. 𝟏𝟔 μM) < Probe superimposition 4 5 6 7 8 40 60 80 100 120 log K sum of matching scores substitution 1 substitution 2 Initial complex (PDBID: 4HW3) … … Step 1: Superimpose the profile to an initial structure Step 2: Obtain pseudo energy score of Cβ positions pseudo energy score ln relative Cβ occupancy Step 3: Calculate matching score by summing up scores of all Cβ positions in the protein 0.7 0.2 0.4 Initial structure Interaction profile (spatial Cβ occupancy) ln Cβ occupancy in profile bulk occupancy 𝒓 𝟎. 𝟓𝟎 1-1. MCL-1 [3] log K sum of matching scores substitution 1 substitution 2 Initial complex (PDBID: 4GIH) … … 𝒓 𝟎. 𝟓𝟎 1-2. TYK2 [4] Diverse protein[2]: Aldo-keto reductase family 1, cathepsin K, azurin, glycoside hydrolase, tyrosyl-tRNA synthetase, … cathepsin K azurin glycoside hydrolase … 5 6 7 8 9 100 150 200 250 𝒓 𝟎. 𝟒𝟓 Quantitative Estimation of Protein-Ligand Substructure Interaction with Inverse Mixed-Solvent Molecular Dynamics Simulation Quantitative Estimation of Protein-Ligand Substructure Interaction with Inverse Mixed-Solvent Molecular Dynamics Simulation