(CBI2023 poster) Quantitative Estimation of Protein-Chemical Substructure Interaction with Inverse Mixed-Solvent Molecular Dynamics

CBI学会2023年大会 ポスター発表 O2-10

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1. Quantitative Estimation of Protein-Chemical Substructure Interaction with Inverse Mixed-Solvent Molecular Dynamics 1. 東工大・情報理工・情工 | Comput. Sci., Sch. Comput., Tokyo Tech 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－化合物部分構造 相互作用 定量的評価手法の開発 This work was partly supported by JSPS KAKENHI (22H03684, 23H03495), NTT Research Inc., and AMED BINDS (JP23ama121026j0002, JP23ama121029j0002). Acknowledgements [1] Yanagisawa, K., Yoshino, R., Kudo, G., Hirokawa, T. IJMS 23: 4749, 2022. [2] Friberg, A., et al. JMC 56: 15-30, 2013. [3] 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) method has been proposed to reveal residue interaction profile of a chemical substructure [1]. Though the profile is helpful to understand the protein-ligand interaction, quantitative evaluation was not proposed. In this study, we define a matching score between a protein and a profile. The score shows r = 0.50 for a 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 N N N OH N N 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 Case 1: Binding affinity prediction (MCL-1 [2]) Correlation coefficient: 𝒓𝒓 = 𝟎𝟎. 𝟓𝟓𝟓𝟓 Case 2: Robustness evaluation of the method (XIAP [3]) The method is robust to side chain-level flexibility Initial complex (PDBID: 5C7A) N +H2 N O N N Cl N Crashed to Lys substitution point score = 29.79 (IC50 = 𝟎𝟎. 𝟔𝟔𝟔𝟔 μM) score = 37.86 (IC50 = 𝟎𝟎. 𝟏𝟏𝟏𝟏 μM) < Probe superimposition 4 5 6 7 8 40 60 80 100 120 −log(Ki ) sum of matching scores substitution 1 substitution 2 Initial complex (PDBID: 4HW3) N O O - S Cl O O - HN Cl O - O O Cl O O - … F F F O Cl … 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