Bacterial Outer Membranes and
Interactions with Membrane Proteins
Wonpil Im
Department of Biological Sciences and
Bioengineering Program
Lehigh University
http://compbio.lehigh.edu
http://www.charmm-gui.org
http://www.glycanstructure.org
Project 1
CHARMM-GUI
EFFECTIVE SIMULATION INPUT GENERATOR AND MORE,
SINCE 2006
CHARMM-GUI provides a web-based graphical user interface to
generate various molecular simulation systems and input files
(for CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS,
Desmond, OpenMM, and CHARMM/OpenMM) to facilitate and
standardize the usage of common and advanced simulation
techniques.
A Way to Share Tools with General Users
458
351
In2015,
260
- 532,079 visitorstoCHARMM-GUI
163
- 279,554 uniquevisitorstoCHARMM-GUI
- 54,960 jobssubmittedtoCHARMM-GUI
7
24
54
87
110
2008 2009 2010 2011 2012 2013 2014 2015 2016
Google Scholar Citations
Scientific Significance
Most simulation communities can utilize the large and unique scope of
CHARMM-GUI functionality to carry out innovative biomedical computational
research, as well as to educate students in a broad range of disciplines.
Year 2011
Let there be light,
so people can come to CHARMM-GUI
Membrane Simulation
Glycoconjugate Simulation
Yuji Sugita / Michael Feig
2.6Matomsin300× 300× 300Å3
Nanoparticle Builder
http://www.colorado.edu/chbe/hendrik-heinz
LayeredSilicates
AluminatesandSulfates
Metals
Apatites
CementMinerals
Project 2
G-LoSA for
Local Structure-centric Biological Studies
Local Structures in Molecular Recognition
Ion binding
Small
Molecule
binding
Protein
Binding
G-LoSA (Graph-based Local Structure Alignment)
Lee and Im (2016) Prot. Sci. 25:865
Lee and Im (2013) J. Chem. Inf. Model 53:2462
Lee and Im (2012) J. Chem. Inf. Model 52:2784
§ Ligand Binding Site Prediction
§ Ligand Structure Prediction
§ Fragment-Based Drug Design
§ Protein-protein interaction prediction
G-LoSA
Search
Alignment of
max. GA-score
Generation of alignments
Iterative maximum
clique search
Fragment
superposition
i
j
k
i
j
k
GA-score = (0,1]
G-LoSA (Graph-based Local Structure Alignment)
Binding Site Prediction
PDB Structure Library
ligand
binding site
pdb 1
G-LoSA
Search
pdb 2
Ligand Structure Prediction
pdb 3
…
…
Project 3
Computational Glycobiology
Computational Glycobiology @ Im Lab
Glycan Structure and Dynamics
Glycolipid Structure and Dynamics
Glycans as Specific Ligands
Bacterial Outer Membrane and Proteins
Bacterial Outer Membranes and
Interactions with Membrane Proteins
Bacterial Outer Membranes
• 10 – 25 repeating units
• each unit with 3-6 linear or
branched sugars
• highly variable
E. coli R1 O6 Lipopolysaccharide
Verified by
Göran Widmalm
Stockholm University
CHARMM-GUI LPS Modeler
CHARMM-GUI LPS Modeler
Kim, Patel, Park, Slusky, Klauda, Widmalm, and Im (2016) Biophys. J. 111:1750-1760
24 lipid A molecules
from 14 different gram-negative bacteria
Nature and linkage type of acyl substituents of the lipid A backbone bound to
GlcN(3N)(II) at position
3'
GlcN(3N)(I) at position
Bacteria
Simulation model
2'
3
Acinetobacter baumannii
Acinetobacter baumannii
ABLIPA
ABLIPB
12:0[3-O(12:0)]
12:0[3-O(12:0)]
14:0[3-O(12:0(2-OH))]
14:0[3-O(12:0(2-OH))]
12:0(3-OH)
12:0(3-OH)
14:0[3-O(12:0)]
14:0(3-OH)
Burkholderia cepacia
Burkholderia cepacia
BCLIPA
BCLIPB
14:0(3-OH)
14:0(3-OH)
16:0[3-O(14:0)]
16:0[3-O(14:0)]
14:0(3-OH)
14:0(3-OH)
16:0(3-OH)
16:0(3-OH)
Campylobacter jejuni
Escherichia coli
Helicobacter pylori
Helicobacter pylori
Klebsiella pneumoniae
Klebsiella pneumoniae
Leptospira interrogans
Neisseria gonorrhoeae
Pseudomonas aeruginosa
Pseudomonas aeruginosa
Salmonella typhimurium
Salmonella typhimurium
Salmonella typhimurium
Shigella flexneri
Vibrio cholerae
Vibrio cholerae
Vibrio cholerae
Yersinia pestis
Yersinia pestis
CJLIPA
ECLIPA
HPLIPB
HPLIPA
KPLIPA
KPLIPB
LILIPA
NGLIPA
PALIPA
PALIPB
STLIPA
STLIPB
STLIPC
SFLIPA
VCLIPA
VCLIPB
VCLIPC
YPLIPA
YPLIPB
14:0[3-O(16:0)]
14:0[3-O(14:0)]
16:0[3-O(14:0)]
14:0[3-O(16:0)]
14:0[3-O(12:0)]
18:0[3-O(18:0)]
18:0[3-O(18:0)]
14:0[3-O(14:0)]
14:0[3-O(14:0)]
14:0[3-O(14:0)]
14:0[3-O(14:0)]
12:0[3-O(14:1)]
16:0[3-O(14:1)]
14:0(3-OH)
14:0[3-O(12:0)]
10:0(3-OH)
12:0[3-O(12:0)]
10:0(3-OH)
12:0[3-O(12:0)]
14:0[3-O(14:0)]
14:0[3-O(12:0)]
14:0[3-O(14:0)]
14:0[3-O(12:0)]
14:0[3-O(14:0)]
14:0[3-O(12:0)]
14:0[3-O(14:0)]
14:0[3-O(12:0)]
12:0[3-O(12:0)]
14:0[3-O(14:0)]
12:0[3-O(12:0[3-Gly])] 14:0[3-O(14:0)]
12:0[3-O(12:0[3-diGly])] 14:0[3-O(14:0)]
14:0[3-O(12:0)]
14:0[3-O(16:1)]
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
16:0(3-OH)
16:0(3-OH)
14:0(3-OH)
14:0(3-OH)
12:0(3-OH)
12:0(3-OH)
10:0(3-OH)
14:0(3-OH)
14:0(3-OH)
18:0(3-OH)
18:0(3-OH)
14:0[3-O(16:0)]
14:0(3-OH)
16:0(3-OH)
14:0[3-O(12:0)]
12:0[3-O(12:0)]
12:0[3-O(12:0)]
14:0[3-O(16:0)]
14:0[3-O(16:0)]
14:0[3-O(16:0)]
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
14:0(3-OH)
12:0(3-OH)
12:0(3-OH)
12:0(3-OH)
14:0(3-OH)
14:0(3-OH)
2
Feature
1 of β-L-Ara4N
2 of β-L-Ara4N
2 of pyrophosphate ethanol amine
My Dream: To Simulate This …
OM
OmpF
OmpLA
LptD-LptE
BamA
AcrAB/TolC
LptA
Lipid II
LptG
LptC
LptF
IM
More work is required to build more realistic
model system including the peptidoglycan layer
LptB
Other Ongoing Simulations: OmpF
In Collaboration with Yuji Sugita @ RIKEN
OmpF in E. coli Outer Membranes
Patel, Re, Wu, Qi, Klebba, Widmalm, Yeom, Sugita, and Im (2016) Biophys. J. 110:930
Lps5-ompf-2
Lipa-ompf
Lps0-ompf
K12-ompf
Acknowledgment
Group Members
Collaborators
Postdoc
graduate
undergraduate
Dr. Roberto De Guzman (KU)
Dr. Soohyung Park
Andrew Beaven
Suwoo Kim
Dr. Huisun Lee
Jumin Lee
Krista Wollerman
Dr. Dhilon Patel
Seonghoon Kim
Russell Caratenuto
Hongjing Ma
Emily Walczyk
Dr. Rich Pastor (NIH)
Joonseong Lee
Dahyun Ko
Dr. Jeff Klauda (UMD)
Dr. Mario Rivera (KU)
Dr. Heather Desaire (KU)
Dr. Alex MacKerell (UMD)
Sang-Jun Park
Dr. Jeff Skolnick (GATECH)
Dr. Jinhyuk Lee
Dr. Taehoon Kim
Vidyashankar Iyer
Dr. Kyu Il Lee
Dr. Huan Rui
Kevin C. Song
Dr. Stanley Opella (UCSD)
Dr. T. Rathinavelan
Dr. Sunhwan Jo
Danielle Stuhlsatz
Dr. Francesca Marassi (Burnham)
Dr. Zhaowen Duan
Dr. Xi Cheng
Phillip Morris
Dr. Roger Koeppe (U Arkansas)
Dr. Jongcheol Jeong
Nathan Kern
Dr. Emilia Wu / Dr. Yifei Qi
Eder M. Contreras
Previous
Current
Dr. Hyun-Suk Lim (POSTECH)
Alfred P. Sloan Fellowship
Meredith Docking Scholarship
Kansas COBRE-PSF Pilot Project
NSF MCB-0918374; MCB-1157677; DBI-1145987
NIH R01 GM092950
HFSP
Dr. Olaf S. Andersen (Cornell)
Bessel Research Award (Humboldt Foundation)
NSF MCB-1516154; DBI-1561372; IIA-1359530
NIH U54-GM087519; R01-GM093258; R01-GM103695
TeraGrid & ANTON
Dr. Satoshi Ishido (RIKEN)
Dr. Tony Kossiakoff (UC)
Dr. Jose Villadangos (WEHI)
Dr. Matthew Call (WEHI)
Dr. Stuart McLaughlin (Stony Brook)