TY - JOUR
T1 - Free Energy Calculations of Microcin J25 Variants Binding to the FhuA Receptor
AU - Lai, Pin Kuang
AU - Kaznessis, Yiannis N.
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/7/11
Y1 - 2017/7/11
N2 - Computer simulations were performed to study the antimicrobial peptide microcin J25 (MJ25), a 21-mer peptide with an unusual lasso structure and high activity against Gram-negative bacteria. MJ25 has intracellular targets. The initial step of MJ25 acquisition in bacterial cells is binding to the outer-membrane receptor FhuA. Molecular dynamics simulations were implemented to study the binding mechanism of MJ25 to FhuA and to search for important binding residues. The absolute binding free energy calculated from combined free energy perturbation and thermodynamic integration methods agrees well with experimental data. In addition, computational mutation analysis revealed that His5 is the key residue responsible for MJ25 and FhuA association. We found that the number of hydrogen bonds is essential for binding of MJ25 to FhuA. This atomistic, quantitative insight sheds light on the mechanism of action of MJ25 and may pave a path for designing active MJ25 analogues.
AB - Computer simulations were performed to study the antimicrobial peptide microcin J25 (MJ25), a 21-mer peptide with an unusual lasso structure and high activity against Gram-negative bacteria. MJ25 has intracellular targets. The initial step of MJ25 acquisition in bacterial cells is binding to the outer-membrane receptor FhuA. Molecular dynamics simulations were implemented to study the binding mechanism of MJ25 to FhuA and to search for important binding residues. The absolute binding free energy calculated from combined free energy perturbation and thermodynamic integration methods agrees well with experimental data. In addition, computational mutation analysis revealed that His5 is the key residue responsible for MJ25 and FhuA association. We found that the number of hydrogen bonds is essential for binding of MJ25 to FhuA. This atomistic, quantitative insight sheds light on the mechanism of action of MJ25 and may pave a path for designing active MJ25 analogues.
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U2 - 10.1021/acs.jctc.7b00417
DO - 10.1021/acs.jctc.7b00417
M3 - Article
AN - SCOPUS:85023188098
SN - 1549-9618
VL - 13
SP - 3413
EP - 3423
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
IS - 7
ER -