Selective Mechanism of Inhibitors to Two Bromodomains of BRD4 Revealed by Multiple Replica Molecular Dynamics Simulations and Free Energy Analyses

Meng Li Xinguo Liu Shaolong Zhang Jiahao Sun Qinggang Zhang Jianzhong Chen

Meng Li, Xinguo Liu, Shaolong Zhang, Jiahao Sun, Qinggang Zhang, Jianzhong Chen. Selective Mechanism of Inhibitors to Two Bromodomains of BRD4 Revealed by Multiple Replica Molecular Dynamics Simulations and Free Energy Analyses[J]. Chinese Journal of Chemical Physics . doi: 10.1063/1674-0068/cjcp2208126
Citation: Meng Li, Xinguo Liu, Shaolong Zhang, Jiahao Sun, Qinggang Zhang, Jianzhong Chen. Selective Mechanism of Inhibitors to Two Bromodomains of BRD4 Revealed by Multiple Replica Molecular Dynamics Simulations and Free Energy Analyses[J]. Chinese Journal of Chemical Physics . doi: 10.1063/1674-0068/cjcp2208126

doi: 10.1063/1674-0068/cjcp2208126

Selective Mechanism of Inhibitors to Two Bromodomains of BRD4 Revealed by Multiple Replica Molecular Dynamics Simulations and Free Energy Analyses

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  • Figure  1.  Molecular structures of inhibitors and proteins: (A) the superimposed structures of BD1 (cyan) with BD2 (orange); (B) the superimposed structures of inhibitor in the binding pocket; (C), (D), and (E), the molecular structures of the inhibitors SG3-179, GSK778, and GSK620 with their potencies (IC50) to BD1 and BD2 of BRD4, respectively.

    Figure  2.  Root-mean-square fluctuations (RMSFs) of the Cα atoms in BD1 and BD2. (A) SG3-179, GSK778, and GSK620 binding to BD1, (B) SG3-179, GSK778, and GSK620 binding to BD2, (C) and (D) are the ZA and BC loops in BD1 and BD2, respectively.

    Figure  3.  Frequency distribution of molecular surface areas of BD1 and BD2. (A) BD1 and (B) BD2.

    Figure  4.  Dynamic cross-correlation matrix reflects the relative motion between residues in BD1 and BD2. (A), (C), and (E) SG3-179, GSK778, and GSK620 bound to BD1, respectively; (B), (D), and (F) SG3-179, GSK778, and GSK620 bound to BD2, respectively.

    Figure  5.  Collective motions of BD1 and BD2 correspond to the first eigenvector PC1. (A), (C), and (E) respectively correspond to SG3-179, GSK778, and GSK620 complexed with BD1; (B), (D), and (F) respectively correspond to SG3-179, GSK778, and GSK620 complexed with BD2.

    Figure  6.  Free energy landscapes of BD1 and BD2 constructed by projecting the MRMD trajectories onto PC1 and PC2: (A) SG3-179 bound to BD1, (B) SG3-179 bound to BD2, (C) GSK778 bound to BD1, (D) GSK778 bound to BD2, (E) GSK620 bound to BD1, and (F) GSK620 bound to BD2.

    Figure  7.  Energy contribution of key residues in BD1 and BD2. (A) SG3-179, (B) GSK778, and (C) GSK620.

    Figure  8.  Energy decomposition of hot spot residues and interactions network in the SG3-179 bound to BD1/BD2. (A, B) SG3-179 bound to BD1, and (C, D) SG3-179 bound to BD2. Hydrogen bonds (green), CH−π (pink) and π−π (hot pink).

    Figure  10.  Energy decomposition of hot spot residues and interactions network in the GSK620 bound to BD1 or BD2. (A, B) GSK620 bound to BD1, and (C, D) GSK620 bound to BD2. Hydrogen bonds (green), CH−π (pink) and π−π (hot pink).

    Figure  9.  Energy decomposition of hot spot residues and interactions network in the GSK778 bound to BD1 or BD2. (A, B) GSK778 bound to BD1, and (C, D) GSK778 bound to BD2. Hydrogen bonds (green), CH−π (pink) and π−π (hot pink).

    Table  I.   Binding free energies of inhibitors to BD1 and BD2 calculated by MM-PBSA method. All values are in kcal/mol.

    Components${\Delta E}_{\rm{ele}}$${\Delta E}_{\rm{vdW}}$${\Delta G}_{\rm{pol}}$${\Delta G}_{\rm{nonpol}}$${\Delta G}_{\rm{ele+pol}}$a${\Delta G}_{\rm{vdW+nonpol}}$b
    SG3-179/BD1 −25.19 ± 0.35 −41.63 ± 0.17 37.90 ± 0.32 −4.21 ± 0.01 12.71 ± 0.15 −45.84 ± 0.12
    SG3-179/BD2 −20.16 ± 0.23 −43.50 ± 0.15 33.42 ± 0.22 −4.60 ± 0.01 13.26 ± 0.14 −48.10 ± 0.11
    GSK778/BD1 −9.22 ± 0.26 −45.53 ± 0.14 26.77 ± 0.25 −4.48 ± 0.01 17.55 ± 0.14 −50.01 ± 0.10
    GSK778/BD2 −8.82 ± 0.19 −44.04 ± 0.15 26.96 ± 0.20 −4.53 ± 0.01 18.14 ± 0.12 −48.57 ± 0.11
    GSK620/BD1 −18.53 ± 0.18 −31.35 ± 0.12 30.44 ± 0.14 −3.66 ± 0.01 11.91 ± 0.15 −35.01 ± 0.09
    GSK620/BD2 −23.84 ± 0.19 −36.07 ± 0.12 34.10 ± 0.14 −3.95 ± 0.01 10.26 ± 0.15 −40.02 ± 0.09
    Components $ \Delta H $ $ -T\Delta S $ ${\Delta G}_{\rm{bind}}$ IC50/(nmol/L) ${\Delta G}_{\rm{exp}}$c
    SG3-179/BD1 −33.13 ± 0.19 21.75 ± 0.64 −11.38 21 −10.57
    SG3-179/BD2 −34.84 ± 0.15 24.14 ± 0.73 −10.70 d
    GSK778/BD1 −32.46 ± 0.17 21.85 ± 0.85 −10.61 40 −10.19
    GSK778/BD2 −30.43 ± 0.14 22.73 ± 0.67 −7.70 6300 −7.16
    GSK620/BD1 −23.10 ± 0.13 16.75 ± 0.67 −6.35 15800 −6.61
    GSK620/BD2 −29.76 ± 0.15 19.85 ± 0.66 −9.91 79 −9.78
    a ${\Delta G}_{\rm{ele+pol}}={\Delta E}_{\rm{ele}}+{\Delta G}_{\rm{pol}}$.
    b ${\Delta G}_{ {\rm{vdW} }+{\rm{nonpol} } }={\Delta E}_{\rm{vdW} }+{\Delta G}_{\rm{nonpol} }$.
    c The experimental values are calculated from the equation: ${\Delta G}_{\rm{exp} }=-RT\ln({\rm{IC} }_{50}$).
    d The IC50 value is not available. available.
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    Table  II.   Hydrogen bonds between inhibitors with BD1 and BD2.

    ComplexesHydrogen bondsaDistance/ÅAngle/(ο)Occupancy/%
    SG3-179/BD1 N140-ND2-HD21···SG3-179-N21 2.96 162.9 99.49
    SG3-179-N23-H19···N140-OD1 3.09 160.8 88.96
    SG3-179-N16-H15···P82-O 3.13 145.3 65.25
    SG3-179/BD2 N433- ND2-HD21···SG3-179-N21 2.98 162.1 99.87
    SG3-179-N23-H19···N433-OD1 2.98 162.2 99.13
    SG3-179-N16-H15···P375-O 3.26 147.0 30.34
    GSK778/BD1 N140-ND2-HD21···GSK778-O26 3.17 154.2 81.38
    N140-ND2-HD22···GSK778-N25 3.18 142.14 74.68
    W81-NE1-HE1···GSK778-O05 2.99 148.7 36.96
    GSK778/BD2 N433- ND2-HD21···GSK778-O26 3.18 149.9 73.64
    N433- ND2-HD21···GSK778-N25 3.23 140.6 57.46
    GSK620/BD1 N140-ND2-HD21···GSK620-O08 2.93 163.3 99.23
    GSK620-N34-H14···N140-OD1 3.01 146.8 91.48
    GSK620/BD2 N433- ND2-HD21···GSK620-O08 2.96 164.3 99.30
    GSK620-N34-H14···N433-OD1 2.93 153.4 99.25
    a Hydrogen bonding is defined as an acceptor···H-donor angle of > 120° and an acceptor···donor distance < 3.5 Å.
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