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. 2023 Jun 29;24(13):10831.
doi: 10.3390/ijms241310831.

Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4

Xiaotang Yang  1 , Yilin Gao  1 , Fuyan Cao  1 , Song Wang  2
Affiliations

Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4

Xiaotang Yang et al. Int J Mol Sci. .

Abstract

Bromodomain-Containing Protein 4 (BRD4) can play an important role in gene transcriptional regulation of tumor development and survival by participating in histone modification epigenetic mechanism. Although it has been reported that novel allosteric inhibitors such as ZL0590 have a high affinity with target protein BRD4 and good efficacy, their inhibitory mechanism has not been studied further. The aim of this study was to reveal the inhibition mechanism of allosteric inhibitor ZL0590 on Free-BRD4 and BRD4 binding MS436 (orthosteric inhibitor) by molecular dynamics simulation combined with a Markov model. Our results showed that BRD4-ZL0590 led to α-helices formation of 100-105 compared with Free-BRD4; the combination of MS436 caused residues 30-40 and 95-105 to form α-helices, while the combination of allosteric inhibitors untangled the α-helices formed by the MS436. The results of Markov flux analysis showed that the binding process of inhibitors mainly involved changes in the degree of α-helices at ZA loop. The binding of ZL0590 reduced the distance between ZA loop and BC loop, blocked the conformation at the active site, and inhibited the binding of MS436. After the allosteric inhibitor binding, the MS436 that could normally penetrate into the interior of the pocket was floating on the edge of the active pocket and did not continue to penetrate into the active pocket as expected. In summary, we provide a theoretical basis for the inhibition mechanism of ZL0590 against BRD4, which can be used as a reference for improving the development of drug targets for cancer therapy.

Keywords: Bromodomain-Containing Protein 4 (BRD4); Markov model; allosteric regulation; conformational changes; molecular dynamics simulations.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure A1
Figure A1
(a)The results of K-means diagrams of Free-BRD4. (b) The results of K-means diagrams of BRD4-ZL0590. (c) The results of K-means diagrams of BRD4-MS436. (d) The results of K-means diagrams of BRD4-MS436-ZL0590.
Figure A2
Figure A2
(a) The lag time determination of Free-BRD4. (b) The lag time determination of BRD4-ZL0590. (c) The lag time determination of BRD4-MS436. (d) The lag time determination of BRD4-MS436-ZL0590.
Figure A3
Figure A3
(a) The results of ck-test of Free-BRD4. (b) The results of ck-test of BRD4-ZL0590. (c) The results of ck-test of BRD4-MS436. (d) The results of ck-test of BRD4-MS436-ZL0590.
Figure A4
Figure A4
(a) The results of PCCA of Free-BRD4. (b) The results of PCCA of BRD4-ZL0590. (c) The results of PCCA of BRD4-MS436. (d) The results of PCCA of BRD4-MS436-ZL0590.
Figure A4
Figure A4
(a) The results of PCCA of Free-BRD4. (b) The results of PCCA of BRD4-ZL0590. (c) The results of PCCA of BRD4-MS436. (d) The results of PCCA of BRD4-MS436-ZL0590.
Figure 1
Figure 1
(A)The hydrogen bonds between the inhibitor MS436 and BRD4. (B) The hydrogen bonds between the allosteric inhibitor ZL0590 and BRD4. (C) The hydrogen bonds between the two inhibitors and BRD4.
Figure 2
Figure 2
(A) The RMSD diagrams of Free-BRD4 and BRD4-ZL0590. (B) The RMSD diagrams of Free-BRD4, BRD4-MS436, and BRD4-MS436-ZL0590. (C) The Rg diagrams of Free-BRD4 and BRD4-ZL0590. (D) The Rg diagrams of Free-BRD4, BRD4-MS436, and BRD4-MS436-ZL0590. (E) The SASA diagrams of Free-BRD4 and BRD4-ZL0590. (F) The SASA diagrams of Free-BRD4, BRD4-MS436, and BRD4-MS436-ZL0590.
Figure 3
Figure 3
(A) The Dynamical Cross-Correlation Matrix diagrams of Free-BRD4 and BRD4-ZL0590. (B) The Dynamical Cross-Correlation Matrix diagrams of Free-BRD4, BRD4-MS436, and BRD4-MS436-ZL0590.
Figure 4
Figure 4
(A) The B-factors diagrams of Free-BRD4 and BRD4-ZL0590. (B) The B-factors diagrams of Free-BRD4, BRD4-MS436, and BRD4-MS436-ZL0590.
Figure 5
Figure 5
(A) The Prody diagrams of Free-BRD4 and BRD4-ZL0590. (B) The Prody diagrams of Free-BRD4, BRD4-MS436, and BRD4-MS436-ZL0590.
Figure 6
Figure 6
(A) The RMSF diagram of Free-BRD4 and BRD4-ZL0590. (B) The RMSF diagram of Free-BRD4, BRD4-MS436, and BRD4-MS436-ZL0590.
Figure 7
Figure 7
(A) The secondary structure changes’ probability of Free-BRD4 and BRD4-ZL0590, BRD4-MS436 and BRD4-MS436-ZL0590 in residues 90–110 and 30–45. (B) The 3D structure changes in the four systems.
Figure 8
Figure 8
Flux analysis of Free-BRD4 (A), BRD4-ZL0590 (B), BRD4-MS436 (C), and BRD4-MS436-ZL0590 (D).
Figure 9
Figure 9
(A) The distance between BC loop and ZA loop of Free-BRD4 and BRD4-ZL0590. (B) The distance between BC loop and ZA loop of Free-BRD4, BRD4-MS436, and BRD4-MS436-ZL0590.
Figure 10
Figure 10
Schematic diagram of changes in active pockets. (A) MS436 in BRD4-MS436. (B) MS436 in BRD4-MS436-ZL0590.
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