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Activity of Antimicrobial Peptide Aggregates Decreases with Increased Cell Membrane Embedding Free Energy Cost
East China Univ Sci & Technol, Sch Chem & Mol Engn, Key Lab Adv Mat, Shanghai 200237, Peoples R China.;East China Univ Sci & Technol, Sch Chem & Mol Engn, Inst Fine Chem, Shanghai 200237, Peoples R China.;KTH Royal Inst Technol, Div Theoret Chem & Biol, Sch Biotechnol, SE-10691 Stockholm, Sweden..
East China Univ Sci & Technol, Sch Chem & Mol Engn, Key Lab Adv Mat, Shanghai 200237, Peoples R China.;East China Univ Sci & Technol, Sch Chem & Mol Engn, Inst Fine Chem, Shanghai 200237, Peoples R China..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-8198-9284
East China Univ Sci & Technol, Sch Chem & Mol Engn, Key Lab Adv Mat, Shanghai 200237, Peoples R China.;East China Univ Sci & Technol, Sch Chem & Mol Engn, Inst Fine Chem, Shanghai 200237, Peoples R China.;Univ Calif Berkeley, Dept Chem & Biomol Engn, 476 Stanley Hall, Berkeley, CA 94720 USA..
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2018 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 57, no 18, p. 2606-2610Article in journal (Refereed) Published
Abstract [en]

Antimicrobial peptides (AMPs) are a promising alternative to antibiotics for mitigating bacterial infections, in light of increasing bacterial resistance to antibiotics. However, predicting, understanding, and controlling the antibacterial activity of AMPs remain a significant challenge. While peptide intramolecular interactions are known to modulate AMP antimicrobial activity, peptide intermolecular interactions remain elusive in their impact on peptide bioactivity. Herein, we test the relationship between AMP intermolecular interactions and antibacterial efficacy by controlling AMP intermolecular hydrophobic and hydrogen bonding interactions. Molecular dynamics simulations and Gibbs free energy calculations in concert with experimental assays show that increasing intermolecular interactions via interpeptide aggregation increases the energy cost for the peptide to embed into the bacterial cell membrane, which in turn decreases the AMP antibacterial activity. Our findings provide a route for predicting and controlling the antibacterial activity of AMPs against Gram-negative bacteria via reductions of intermolecular AMP interactions.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2018. Vol. 57, no 18, p. 2606-2610
National Category
Biophysics
Identifiers
URN: urn:nbn:se:kth:diva-228427DOI: 10.1021/acs.biochem.8b00052ISI: 000431927100008PubMedID: 29638118Scopus ID: 2-s2.0-85046780456OAI: oai:DiVA.org:kth-228427DiVA, id: diva2:1210708
Note

QC 20180529

Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2019-05-10Bibliographically approved
In thesis
1. Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
Open this publication in new window or tab >>Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on studies of protein-ligand systems using enhanced sampling methods. In chapter I, I give a brief introduction to the time-scale problem and some enhanced sampling methods. In chapter II, the basics of MD simulation are reviewed. In chapter III, the theoretical backgrounds of umbrella sampling, bias-exchange metadynamics and infrequent metadynamics are presented. In chapter IV, the 5 papers included in this thesis are summarized. In paper 1, we studied the relationship between the antibacterial activities of antimicrobial peptides and their aggregation propensities. We found that an increasing aggregation propensity increases the free energy cost of peptide embedding into the bacterial membrane and decreases antibacterial activity. In paper 2, we employed the umbrella sampling approach to obtain the free energy landscape of Pittsburgh compound-B penetrating into the core binding sites of amyloid βfibrils. Our study suggested that, for the design of probes binding to fibril like proteins, other than the binding affinity, the dynamics of probes in the fibrils should also be considered. In paper 3, we studied the coupled folding and binding process of the intrinsically disordered protein p53 to MDM2 with bias-exchange metadynamics and infrequent metadynamics. We reconstructed the free energy landscape and built a kinetic network for this process. In paper 4, we studied the binding modes of ASEM with a chimera structure of α7 nicotinic acetylcholine receptor with well-tempered metadynamics. We found that an important residue, Trp53, can significantly affect the stabilities of the binding modes. In paper 5, we proposed an efficient method to estimate the transition times of rare events in biomolecular systems. In chapter V, I present a conclusion of this thesis and propose an outlook related to the selection of collective variables for enhanced sampling methods.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019. p. 58
Series
TRITA-CBH-FOU ; 34
Keywords
molecular dynamics, enhanced sampling, protein-ligand interactions, umbrella sampling, metadynamics
National Category
Natural Sciences
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-251025 (URN)
Public defence
2019-06-05, FP41, Roslagstullsbacken 33, Byggnad 1, floor 4, AlbaNova, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 2019-05-10

Available from: 2019-05-10 Created: 2019-05-08 Last updated: 2019-05-10Bibliographically approved

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