TY - JOUR
T1 - Molecular Dynamics Investigation into the Effect of Zinc(II) on the Structure and Membrane Interactions of the Antimicrobial Peptide Clavanin A
AU - Duay, Searle S.
AU - Sharma, Gaurav
AU - Prabhakar, Rajeev
AU - Angeles-Boza, Alfredo M.
AU - May, Eric R.
N1 - Funding Information:
*E-mail: alfredo.angeles-boza@uconn.edu. Phone: (860) 486-6718 (A.M.A.-B.). *E-mail: eric.may@uconn.edu. Phone: (860) 486-0484 (E.R.M.). ORCID Searle S. Duay: 0000-0002-0382-1053 Rajeev Prabhakar: 0000-0003-1137-1272 Alfredo M. Angeles-Boza: 0000-0002-5560-4405 Eric R. May: 0000-0001-8826-1990 Author Contributions The manuscript was written through contributions of all authors. Funding This work was supported by the grants from the National Science Foundation (grant MCB1715494 to AMA-B and grant CHE-1664926 to RP) and the National Institutes of Health (grant R35GM119762 to ERM). Computational resources have been provided by the NSF XSEDE program (grant TG-MCB170151). Notes The authors declare no competing financial interest.
PY - 2019/4/18
Y1 - 2019/4/18
N2 - Clavanin A (ClavA) is an antimicrobial peptide (AMP) whose antimicrobial activity is enhanced in the presence of Zn(II) ions. The antimicrobial activity of ClavA has been shown to increase 16-fold in the presence of Zn(II) ions. In this study, we investigate the potential sources of this enhancement, namely, the effect of Zn(II) binding on the helical conformation of ClavA and on the ClavA interaction with a model for gram-negative bacterial membranes. In addition, we investigate the effect of Zn(II) on the membrane mechanical properties. We employed all-atom equilibrium molecular dynamics simulations initiated from both fully helical and random coil structures of ClavA. We observe that Zn(II) can stabilize an existing helical conformation in the Zn(II)-binding region, but we do not observe induction of helical conformations in systems initiated in random coil configurations. Zn(II) binding to ClavA provides more favorable electrostatics for membrane association in the C-terminal region. This is evidenced by longer and stronger C-terminal-lipid interactions. Zn(II) is also capable of modulating the membrane properties in a manner which favors ClavA insertion and the potential for enhanced translocation into the cell. This work provides insights into the role of divalent metal cations in the antimicrobial activity of ClavA. This information can be used for the development of synthetic AMPs containing motifs that can bind metals (metalloAMPs) for therapeutic and medical purposes.
AB - Clavanin A (ClavA) is an antimicrobial peptide (AMP) whose antimicrobial activity is enhanced in the presence of Zn(II) ions. The antimicrobial activity of ClavA has been shown to increase 16-fold in the presence of Zn(II) ions. In this study, we investigate the potential sources of this enhancement, namely, the effect of Zn(II) binding on the helical conformation of ClavA and on the ClavA interaction with a model for gram-negative bacterial membranes. In addition, we investigate the effect of Zn(II) on the membrane mechanical properties. We employed all-atom equilibrium molecular dynamics simulations initiated from both fully helical and random coil structures of ClavA. We observe that Zn(II) can stabilize an existing helical conformation in the Zn(II)-binding region, but we do not observe induction of helical conformations in systems initiated in random coil configurations. Zn(II) binding to ClavA provides more favorable electrostatics for membrane association in the C-terminal region. This is evidenced by longer and stronger C-terminal-lipid interactions. Zn(II) is also capable of modulating the membrane properties in a manner which favors ClavA insertion and the potential for enhanced translocation into the cell. This work provides insights into the role of divalent metal cations in the antimicrobial activity of ClavA. This information can be used for the development of synthetic AMPs containing motifs that can bind metals (metalloAMPs) for therapeutic and medical purposes.
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U2 - 10.1021/acs.jpcb.8b11496
DO - 10.1021/acs.jpcb.8b11496
M3 - Article
C2 - 30908921
AN - SCOPUS:85064348132
VL - 123
SP - 3163
EP - 3176
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
SN - 1520-6106
IS - 15
ER -