TY - JOUR
T1 - Molecular basis of the selectivity of the immunoproteasome catalytic subunit LMP2-specific inhibitor revealed by molecular modeling and dynamics simulations
AU - Lei, Beilei
AU - Abdul Hameed, Mohamed Diwan M.
AU - Hamza, Adel
AU - Wehenkel, Marie
AU - Muzyka, Jennifer L.
AU - Yao, Xiao Jun
AU - Kim, Kyung Bo
AU - Zhan, Chang Guo
PY - 2010/9/30
Y1 - 2010/9/30
N2 - Given that immunoproteasome inhibitors are currently being developed for a variety of potent therapeutic purposes, the unique specificity of an α′,β′-epoxyketone peptide (UK101) toward the LMP2 subunit of the immunoproteasome (analogous to β5 subunit of the constitutive proteasome) has been investigated in this study for the first time by employing homology modeling, molecular docking, molecular dynamics simulation, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. On the basis of the simulated binding structures, the calculated binding free energies are in qualitative agreement with the corresponding experimental data, and the selectivity of UK101 is explained reasonably. The observed selectivity of UK101 for the LMP2 subunit is rationalized by the requirement for both a linear hydrocarbon chain at the N terminus and a bulky group at the C terminus of the inhibitor, because the LMP2 subunit has a much more favorable hydrophobic pocket interacting with the linear hydrocarbon chain, and the bulky group at the C terminus has a steric clash with the Tyr 169 in β5 subunit. Finally, our results help to clarify why UK101 is specific to the LMP2 subunit of immunoproteasome, and this investigation should be valuable for rational design of more potent LMP2-specific inhibitors.
AB - Given that immunoproteasome inhibitors are currently being developed for a variety of potent therapeutic purposes, the unique specificity of an α′,β′-epoxyketone peptide (UK101) toward the LMP2 subunit of the immunoproteasome (analogous to β5 subunit of the constitutive proteasome) has been investigated in this study for the first time by employing homology modeling, molecular docking, molecular dynamics simulation, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. On the basis of the simulated binding structures, the calculated binding free energies are in qualitative agreement with the corresponding experimental data, and the selectivity of UK101 is explained reasonably. The observed selectivity of UK101 for the LMP2 subunit is rationalized by the requirement for both a linear hydrocarbon chain at the N terminus and a bulky group at the C terminus of the inhibitor, because the LMP2 subunit has a much more favorable hydrophobic pocket interacting with the linear hydrocarbon chain, and the bulky group at the C terminus has a steric clash with the Tyr 169 in β5 subunit. Finally, our results help to clarify why UK101 is specific to the LMP2 subunit of immunoproteasome, and this investigation should be valuable for rational design of more potent LMP2-specific inhibitors.
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U2 - 10.1021/jp1058098
DO - 10.1021/jp1058098
M3 - Article
C2 - 20812720
AN - SCOPUS:77957130089
SN - 1520-6106
VL - 114
SP - 12333
EP - 12339
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 38
ER -