Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5
Abstract
:1. Introduction
2. Simulation Methods
2.1. Model Preparation
2.2. Molecular Dynamics Simulation
2.3. MM-PBSA Calculation
2.4. Analysis
3. Result and Discussion
3.1. Analysis of Enzyme-Substrate Binding Pattern
3.2. Factors That Stabilize Substrate Binding
3.3. Binding Free Energy Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Complex | The Recipient and the Donor | Ratio (%) |
---|---|---|
CYP3A4-MDZ | heme@O1A-105R@HH21-NH2 | 65.1 |
heme@O2D-105R@HH22-NH2 | 83.9 | |
heme@O2D-105R@HH12-NH1 | 77.4 | |
heme@O1D-126W@HE1-NE1 | 92.5 | |
heme@O2D-126W@HE1-NE1 | 75.5 | |
heme@O1D-130R@NH11-NH1 | 94.0 | |
heme@O1A-375R@NH12-NH1 | 76.5 | |
heme@O1A-375R@NH22-NH2 | 86.6 | |
heme@O2A-375R@NH22-NH2 | 89.5 | |
heme@O2A-375R@NH12-NH1 | 52.9 | |
MDZ@NAN-119S@HG-OG | 93.8 | |
CYP3A5-MDZ | heme@O1D-105R@HH22-NH2 | 68.4 |
heme@O2A-105R@HH21-NH2 | 52.1 | |
heme@O1A-105R@HH21-NH2 | 43.4 | |
heme@O2A-105R@HE-NE | 34.8 | |
heme@O1A-105R@HE-NE | 31.4 | |
heme@O2D-105R@HH22-NH2 | 33.5 | |
heme@O1D-126W@HE1-NE1 | 90.7 | |
heme@O2D-126W@HE1-NE1 | 85.5 | |
heme@O2D-130R@NH11-NH1 | 50.7 | |
MDZ@NAN-119S@HG-OG | 77.9 |
Complex | Salt Bridge Action | Ratio (%) |
---|---|---|
CYP3A4-MDZ | 374E@OE1-106R@HH12-NH1 | 67.30 |
374E@OE1-106R@HH11-NH1 | 67.30 | |
374E@OE2-106R@HH12-NH1 | 61.57 | |
374E@OE2-106R@HH11-NH1 | 61.57 | |
374E@OE2-106R@HE-NE | 43.03 | |
374E@OE1-106R@HE-NE | 54.53 | |
441N@OD1-130R@HH22-NH2 | 96.40 | |
441N@OD1-130R@HH21-NH2 | 96.40 | |
441N@OD1-130R@HH12-NH1 | 89.17 | |
441N@OD1-130R@HH11-NH1 | 89.17 | |
441N@ND2-130R@HH22-NH2 | 37.70 | |
441N@ND2-130R@HH21-NH2 | 37.70 | |
CYP3A5-MDZ | 76E@OE1-106R@HH12-NH1 | 87.37 |
76E@OE1-106R@HH11-NH1 | 87.37 | |
76E@OE1-106R@HH22-NH2 | 88.67 | |
76E@OE1-106R@HH21-NH2 | 88.67 | |
76E@OE2-106R@HH12-NH1 | 79.87 | |
76E@OE2-106R@HH11-NH1 | 79.87 | |
76E@OE2-106R@HH22-NH2 | 64.03 | |
76E@OE2-106R@HH21-NH2 | 64.03 | |
374E@OE2-106R@HH12-NH1 | 33.97 | |
374E@OE2-106R@HH11-NH1 | 33.97 | |
374E@OE1-106R@HH12-NH1 | 32.73 | |
374E@OE1-106R@HH11-NH1 | 32.73 |
Complex | Residue | Score |
---|---|---|
CYP3A4-MDZ | Phe108 | −1.056 |
Ala117 | 1.311 | |
Ile120 | 0.056 | |
Phe215 | 0.322 | |
Leu216 | 0.211 | |
Pro218 | 0.733 | |
Phe304 | 1.744 | |
Ala305 | 1.167 | |
Ile369 | 0.889 | |
Ala370 | 1.000 | |
Leu482 | 0.133 | |
CYP3A5-MDZ | Leu120 | −0.022 |
Leu211 | −0.067 | |
Ala297 | 1.167 | |
Val369 | 1.144 | |
Ala370 | 1.256 |
3A4-MDZ | 3A5-MDZ | |
---|---|---|
∆Eele | −15.5 ± 2.5 | −12.0 ± 2.7 |
∆Evdw | −38.3 ± 2.7 | −30.5 ± 2.2 |
∆GPB | 23.5 ± 1.5 | 19.9 ± 1.8 |
∆GSA | −4.3 ± 0.2 | −3.3+0.2 |
∆Ggas | −53.8 ± 3.5 | −42.5 ± 3.6 |
∆Gsolv | 19.2 ± 1.5 | 16.6 ± 1.7 |
a ∆Gpol | 8.00 | 7.95 |
b ∆Gnonpol | −43.6 | −33.8 |
c ∆GMMPB/SA | −34.6 ± 2.9 | −25.8 ± 2.5 |
T∆S | −15.1 ± 7.4 | −14.2 ± 5.5 |
d ∆Gbind | −19.5 | −11.6 |
Residue | ∆Evdw | ∆Eele | ∆GPB | ∆GSA | ∆Gbind |
---|---|---|---|---|---|
Leu216 | −0.77 ± 0.57 | −0.15 ± 0.27 | 0.61 ± 0.30 | −0.36 ± 0.06 | −2.67 ± 0.64 |
Ser119 | −0.28 ± 0.58 | −3.74 ± 0.98 | 1.90 ± 0.28 | −0.09 ± 0.03 | −2.20 ± 0.59 |
Leu482 | −1.29 ± 0.31 | −0.12 ± 0.07 | 0.19 ± 0.05 | −0.23 ± 0.06 | −1.45 ± 0.34 |
Ala370 | −1.17 ± 0.26 | −0.03 ± 0.05 | 0.19 ± 0.08 | −0.23 ± 0.05 | −1.23 ± 0.27 |
Phe304 | −1.10 ± 0.38 | −0.07 ± 0.07 | 0.37 ± 0.14 | −0.16 ± 0.04 | −0.96 ± 0.32 |
Ile369 | −0.70 ± 0.27 | −0.08 ± 0.07 | 0.05 ± 0.07 | −0.05 ± 0.02 | −0.78 ± 0.27 |
Arg105 | −0.64 ± 0.31 | −1.43 ± 0.42 | 1.47 ± 0.40 | −0.07 ± 0.03 | −0.66 ± 0.41 |
Asp217 | −0.83 ± 0.23 | −1.13 ± 0.34 | 1.54 ± 0.46 | −0.12 ± 0.03 | −0.54 ± 0.23 |
Ile301 | −0.51 ± 0.13 | −0.17 ± 0.09 | 0.21 ± 0.09 | −0.03 ± 0.01 | −0.50 ± 0.13 |
Thr309 | −0.43 ± 0.13 | −0.08 ± 0.10 | −0.08−0.08 | −0.05 ± 0.02 | −0.50 ± 0.13 |
Ala305 | −0.41 ± 0.18 | −0.09 ± 0.07 | −0.07−0.05 | −0.03 ± 0.02 | −0.42 ± 0.17 |
HEM | −5.12 ± 0.63 | −0.88 ± 0.56 | 1.72 ± 0.42 | −0.35 ± 0.04 | −4.62 ± 0.76 |
Residue | ∆Evdw | ∆Eele | ∆GPB | ∆GSA | ∆Gbind |
---|---|---|---|---|---|
Ser119 | −0.71 ± 0.65 | −3.78 ± 0.84 | 2.15 ± 0.30 | −0.15 ± 0.04 | −2.49 ± 0.52 |
Thr302 | −1.68 ± 0.45 | −0.21 ± 0.22 | 0.45 ± 0.21 | −0.26 ± 0.04 | −1.70 ± 0.49 |
Phe297 | −1.36 ± 0.47 | −0.36 ± 0.16 | 0.68 ± 0.21 | −0.19 ± 0.05 | −1.23 ± 0.43 |
Arg105 | −0.68 ± 0.19 | −0.49 ± 0.44 | 0.48 ± 0.39 | −0.05 ± 0.02 | −0.74 ± 0.37 |
Leu211 | −0.55 ± 0.21 | −0.08 ± 0.05 | 0.18 ± 0.07 | −0.18 ± 0.05 | −0.63 ± 0.23 |
Ala370 | −0.50 ± 0.23 | −0.02 ± 0.07 | 0.16 ± 0.10 | −0.14 ± 0.05 | −0.50 ± 0.24 |
Val369 | −0.51 ± 0.22 | −0.02 ± 0.18 | 0.14 ± 0.20 | 0.07 ± 0.03 | −0.47 ± 0.24 |
Ala298 | −0.44 ± 0.14 | −0.08 ± 0.05 | 0.16 ± 0.08 | −0.02 ± 0.01 | −0.39 ± 0.15 |
HEM | −5.12 ± 0.75 | −1.29 ± 0.69 | 2.48 ± 0.88 | −0.39 ± 0.05 | −4.32 ± 0.70 |
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Liu, S.; Zheng, Q.; Bai, F. Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5. Molecules 2023, 28, 6900. https://doi.org/10.3390/molecules28196900
Liu S, Zheng Q, Bai F. Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5. Molecules. 2023; 28(19):6900. https://doi.org/10.3390/molecules28196900
Chicago/Turabian StyleLiu, Shuhui, Qingchuan Zheng, and Fuquan Bai. 2023. "Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5" Molecules 28, no. 19: 6900. https://doi.org/10.3390/molecules28196900