LI Jianguo

Conformational Transitions of Melittin between Aqueous and Lipid Phases: Comparison of Simulations with Experiments

Published date : 16 Aug 2018

Peptides are promising drug candidates with advantageous therapeutic properties. However, their inherent flexibility makes the development of structure−activity relationships difficult. Molecular dynamics simulations have been widely used to study peptide conformations, but they are limited by force field parameters.

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Journal Paper
journal
The Journal of Physical Chemistry B, 2018, doi: 10.1021/acs.jpcb.8b06781
Impact Factor
3.146

Reactive Metabolite-induced Protein Glutathionylation: a Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity

Published date : 13 Jul 2018

Although covalent protein binding is established as the pivotal event underpinning acetaminophen (APAP) toxicity, its mechanistic details remain unclear. In this study, we demonstrated that APAP induces widespread protein glutathionylation in a time-, dose- and bioactivation-dependent manner in HepaRG cells.

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Journal Paper
journal
Molecular & Cellular Proteomics, 2018, Jul 13, doi: 10.1074/mcp.RA118.000875
Impact Factor
5.232

Antimicrobial activity profiles of Amphiphilic Xanthone derivatives are a function of their molecular Oligomerization

Published date : 18 May 2018

Currently, membrane-targeting small antimicrobial peptidomimetics (SAP) are important in antibiotic development because bacteria appear to develop resistance to these surface-active compounds less readily. However, the molecular membrane-targeting action of SAPs has received little attention. In this study, we investigated the effect of oligomerization of amphiphilic xanthone, a model SAP, on its antimicrobial properties against both Gram-positive and Gram-negative bacteria.

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Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018, doi: 10.1016/j.bbamem.2018.05.006
Impact Factor
3.498

Elucidating the bactericidal mechanism of action of the linear antimicrobial tetrapeptide BRBR-NH2

Published date : 11 May 2018

Linear antimicrobial peptides, with their rapid bactericidal mode of action, are well-suited for development as topical antibacterial drugs. We recently designed a synthetic linear 4-residue peptide, BRBR-NH2, with potent bactericidal activity against Staphylococcus aureus (MIC 6.25 μM), the main causative pathogen of human skin infections with an unknown mechanism of action.

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Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018, doi: 10.1016/j.bbamem.2018.05.004
Impact Factor
3.498

The effect of molecular shape on oligomerization of hydrophobic drugs: molecular simulations of ciprofloxacin and Nutlin

Published date : 13 Mar 2018

Molecular aggregation plays a significant role in modulating the solubility, permeability, and bioactivity of drugs. The propensity to aggregate depends on hydrophobicity and on molecular shape. Molecular dynamics simulations coupled with enhanced sampling methods are used to explore the early stages of oligomerization of two drug molecules which have a strong aggregation propensity, but with contrasting molecule shapes: the antibiotic ciprofloxacin and the anticancer drug Nutlin-3A. The planar shape of ciprofloxacin induces the formation of stable oligomers at all cluster sizes.

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Journal Paper
journal
The Journal of Chemical Physics 148, 104902 (2018); doi: 10.1063/1.5013056
Impact Factor
2.965

Molecular Insights into the Membrane Affinities of Model Hydrophobes

Published date : 01 Mar 2018

Membrane-active antibiotics are of great interest in fighting bacterial resistance. α-Mangostin is a membrane-active molecule, but there are no details of its mechanism of action at the atomistic level. We have employed free-energy simulations and microsecond-long conventional molecular dynamics simulations to study the mode of interaction of α-mangostin with a model bacterial membrane and compare it with the mechanisms of three hydrophobic molecules (ciprofloxacin, xanthone, and tetracycline).

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Journal Paper
journal
ACS Omega 2018, 3, Pg. 2498-2507, doi: 10.1021/acsomega.7b01759

Characterizing the Conformational Landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations

Published date : 15 Nov 2017

The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the ‘conformational selection’ paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by ‘binding induced folding’.

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Journal Paper
journal
Scientific Reports 7, Article no:15600, 2017, doi:10.1038/s41598-017-15930-4
Impact Factor
4.259

Molecular Environment Modulates Conformational Differences between Crystal and Solution States of Human beta-defensin 2

Published date : 15 Mar 2017

Human β-defensin 2 is a cysteine-rich antimicrobial peptide. In the crystal state, the N-terminal segment (residues 1−11) exhibits a helical conformation. However, a truncated form, with four amino acids removed from the N-terminus, adopts nonhelical conformations in solution, as shown by NMR. To explore the molecular origins of these different conformations, we performed Hamiltonian replica exchange molecular dynamics simulations of the peptide in solution and in the crystal state.

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Journal Paper
journal
Journal of Physical Chemistry Part B, 2017, doi : 10.1021/acs.jpcb.7b00083
Impact Factor
3.177

Membrane Active Antimicrobial Peptides: Translating Mechanistic Insights to Design

Published date : 14 Feb 2017

Antimicrobial peptides (AMPs) are promising next generation antibiotics that hold great potential for combating bacterial resistance. AMPs can be both bacteriostatic and bactericidal, induce rapid killing and display a lower propensity to develop resistance than do conventional antibiotics. Despite significant progress in the past 30 years, no peptide antibiotic has reached the clinic yet. Poor understanding of the action mechanisms and lack of rational design principles have been the two major obstacles that have slowed progress.

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Journal Paper
journal
Frontiers in Neuroscience, Feb 2017, Vol. 11, Article 73, doi: 10.3389/fnins.2017.00073
Impact Factor
3.398

Stabilization of Peptides against Proteolysis through Disulfide-Bridged Conjugation with Synthetic Aromatics

Published date : 01 Feb 2017

Peptides have been promising molecular scaffolds for the development of potential therapeutics with high affinity and specificity to biomacromolecules. However, their inherent proteolytic instability significantly hampers their biological applications. Strategies that can stabilize peptides against proteolytic digestion on the basis of noncovalent interactions—without extensive manipulation of the sequence or use of unnatural residues—are greatly desired.

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Journal Paper
journal
Organic & Biomolecular Chemistry, 2017, Issue 15, Pg 1921-1929, doi: 10.1039/C6OB02786E
Impact Factor
3.559