Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes
<p>Exemplary complex structures of trypsin-like serine proteases. (<b>A</b>) KLK4 complex with a highly potent SFTI-1 variant (cyan), containing Arg5 instead of the natural Lys5, as well as the mutations Phe2, Gln4, and Asn14 (<b>upper panel</b>). The lower panel shows a close-up of the active site, in which the P4 to P2′ residues of the SFTI variant bind to the corresponding S4 to S2′ specificity pockets as other canonical inhibitors similar to substrates via the standard mechanism. (<b>B</b>) Human α-thrombin in complex with the extremely strong inhibitor hirudin (green), an anticoagulant from the leech <span class="html-italic">Hirudo medicinalis</span> (<b>upper panel</b>). In contrast to canonical inhibitors hirudin binds in a reverse manner, with the N-terminal Ile1 occupying the S2 subsite, Thr2 the S1 subsite, and Tyr3 the S4 subsite (<b>lower panel</b>). However, Asp49 to Asn52 of hirudin correspond to P1′ to P4′ residues and bind the S1′ to S4′ subsites like canonical inhibitors, whereby further protease–inhibitor interactions occur in the prime side.</p> "> Figure 2
<p>Plot of K<sub>i</sub> values (nM) in logarithmic scale versus ΔG (kJ) for serine protease inhibitor complexes. The round symbols represent experimental K<sub>i</sub> and ΔG values from protease–inhibitor pairs, while the diamonds belong to calculated K<sub>i</sub> (K<sub>D</sub>) and ΔG derived from protease inhibitor complex coordinates: β-Try/PABA, Try-3/bikunin-D2, matriptase-SFTI, plasmin-SFTI, β-Try/SFTI-TCTR-N12-N14, KLK4/SFTI-FCQR-N14, β-Try/BPTI, and α-thrombin/hirudin (more β-Try structures with SFTI-1 variants are available). Essentially, free interaction energies were calculated with the YASARA plugin FoldX or with the web server PRODIGY. Overall, the FoldX results for serine protease inhibitor complexes correlated better with the experimental data. More details can be found in <a href="#ijms-25-02429-t001" class="html-table">Table 1</a>.</p> "> Figure 3
<p>Examples of cysteine, aspartic and metalloproteases. (<b>A</b>) SARS-CoV-2 MPro is a chymotrypsin-like protease with a catalytic dyad (His41, Cys145) in the half domains I and II, while domain III mediates dimerization (PDB 7RNW). The synthetic, cyclo-14-mer inhibits with a K<sub>i</sub> of roughly 4 nM. (<b>B</b>) Aspartic HIV protease forms a symmetrical active dimer, which binds a synthetic cyclo9-mer exhibiting an estimated K<sub>i</sub> of 3 nM (PDB 7YF6). (<b>C</b>) The catalytic domain of MMP-14 (MT1-MMP) binds the natural proteinaceous inhibitor TIMP-2 via a tight interaction to Zn<sup>2+</sup> from the N-terminal Cys1 and Thr2 in the S1′ pocket (PDB 1BUV), exhibiting a K<sub>i</sub> of 104 pM.</p> "> Figure 4
<p>Plot of K<sub>i</sub> values (nM) in logarithmic scale versus ΔG (kJ) for cysteine, aspartic and metallo-protease inhibitor complexes. The round symbols represent experimental K<sub>i</sub> and ΔG values from protease–inhibitor pairs, while the diamonds and triangles belong to calculated K<sub>i</sub> (K<sub>D</sub>) and ΔG derived from calculations with the YASARA plugin FoldX and the PRODIGY web server, respectively. The protease inhibitor complexes were legumain/cystatin E, SARS-CoV-2 Mpro/cyclo-14-mer, BACE-1/22-mer, HIV protease/cyclo-9-mer, MMP-14/TIMP-2, and MMP-3/TIMP-1. In five cases the correlation of experimental data was better with PRODIGY results. The cystatin E-K75A constant (19.8 nM) for human legumain corresponds better to the one derived from the coordinates of the structural data (46.4 kJ/mol) compared with the reported 0.011 nM. A better correlation was seen for energy minimized coordinates of the BACE-1 complex (−47.28 kJ/mol). More details can be found in <a href="#ijms-25-02429-t001" class="html-table">Table 1</a>.</p> ">
Abstract
:1. Introduction
2. Results and Discussion
β-Trypsin/SFTI-1 | Measured Ki [nM] | FoldX Ki [nM] | PRODIGY KD [nM] |
---|---|---|---|
SFTI-1 | 0.017 | 0.007 | 0.963 |
SFTI-P14 | - | 0.766 | 1.4 |
SFTI-R5 | 0.027 | - | 0.99 |
SFTI-TCTR-N12N14 | 0.7 | 2.86 | - |
SFTI-RCTR | 4.7 | ||
SFTI-RCTK | 9.9 | ||
SFTI-TCTK | 5.5 | ||
SFTI-TCTK-P14 | 1.6 | ||
SFTI-TCTR-P14 | 0.43 | ||
Thrombin/hirudin | Measured Ki [fM] | FoldX Ki [fM] | PRODIGY KD [fM] |
hirudin-v1/v2 | 22 | 19 | - |
rhir-v1 | 180 | - | - |
rhir-v1-Trp3 | 60 | - | - |
rhir-v1-Phe3 | 30 | - | - |
hirudin-v2 | 15 | - | |
v2-Trp3 | 0.077 | - | |
v2-Arg1-Trp3 | 0.021 | - |
3. Material and Methods
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Complex | FoldX ΔG | Ki (exp) | ΔG (exp) | ΔG Prodigy | Structure | ||
---|---|---|---|---|---|---|---|
Protease/Inhibitor | kJ/mol | kcal/mol | nM | nM | kJ/mol | kJ/mol | PDB |
β-Try/PABA | −29.02 | −6.93 | 8220 | 6100 [25] | −29.79 | −23.93 1 | 3GY4 [26] |
Try-3/bikunin-D2 | −40.96 | −9.79 | 78 | 138 [27] | −39.87 | −43.10 | 4U30 [27] |
matriptase/SFTI-1 | −48.02 | −11.47 | 3.83 | 0.92 [28] | −51.55 | −39.75 | 3P8F [29] |
plasmin/SFTI-Y4K5R7N14 | −50.41 | −12.04 | 1.46 | 1.20 [30] | −50.98 | −54.03 | 6D3Z [30] |
β-Try/SFTI-T2R5N12N14 | −48.74 | −11.65 | 2.86 | 0.70 [15] | −52.23 | −48.53 | 6BVH [15] |
KLK4/SFTI-F2Q4R5N14 | −58.95 | −14.09 | 0.046 | 0.039 [31] | −59.40 | (−41.84) | 4KEL [31] |
β-Try/SFTI-1 | −63.18 | −15.10 | 0.0066 | 0.017 [32] | −61.47 | (−51.46) | 1SFI [33] |
β-Try/BPTI | −61.42 | −14.68 | 0.017 | 0.00006 [34] | −75.43 | (−51.46) | 2PTC [35] |
α-thrombin/hirudin-v2 | −78.95 | −18.87 | 0.000015 | 0.000022 [36] | −77.91 | (−49.37) | 4HTC [37] |
legumain/cystatin E | (−31.88) | −7.62 | 46.4/19.8 2 | 0.0107 [38] | −62.59/43.95 2 | −41.84 | 4N6O [39] |
MPro/cyclo-14-mer | (−30.46) | −7.28 | 17 | 14 [40] | −44.81 | −44.33 | 7RNW [40] |
BACE-1/22-mer | −53.68 | −12.83 | 0.39/10.0 | 3.2 3 [41] | −48.46 | −45.60/47.28 | 5MCQ [41] |
HIV/cyclo-9-mer | −51.97 | −12.42 | 0.779 | 4.02 3 [42] | −47.90 | (−36.00) | 7YF6 [42] |
MMP-14/TIMP-2 | −52.09 | −12.45 | 0.740/0.149 | 0.104 [43] | −56.95 | −56.07 | 1BUV [44] |
MMP-3/TIMP-1 | (−65.90) | −15.75 | 0.003/0.087 4 | 0.130 [45] | −56.40 | −57.32 4 | 1UEA [46] |
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Goettig, P.; Chen, X.; Harris, J.M. Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes. Int. J. Mol. Sci. 2024, 25, 2429. https://doi.org/10.3390/ijms25042429
Goettig P, Chen X, Harris JM. Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes. International Journal of Molecular Sciences. 2024; 25(4):2429. https://doi.org/10.3390/ijms25042429
Chicago/Turabian StyleGoettig, Peter, Xingchen Chen, and Jonathan M. Harris. 2024. "Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes" International Journal of Molecular Sciences 25, no. 4: 2429. https://doi.org/10.3390/ijms25042429