Digital biology: protein-ligand

interactions
Nanomaterials: proteins and water, cell membranes

Key issue: modulation of dielectric effect by hydrophobic groups

L. Ridgway Scott
The Institute for Biophysical Dynamics, the Computation Institute, and the
Departments of Computer Science and Mathematics, The University of Chicago.
Last year at the IMA, Univ. of Minnesota (thanks to NSF).

This talk is based on joint work with Wah Chiu (Baylor College of Medicine),
Ariel Ferndandez (Rice Univ.), Andy McCammon (UCSD), Kristina Rogale
Plazonic (Princeton), Harold Scheraga (Cornell), and and at U. Chicago: Steve
Berry, Peter Brune, Chris Fraser, and Matt Knepley.

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1 Ligand binding removes water: dehydrons

CHn CHn
CHn CHn CHn
CHn
C N C O H N
O H

H O
O H H
L IG A N D
H
Binding of ligand changes underprotected hydrogen
bond (high dielectric) to strong bond (low dielectric)
No intermolecular bonds needed!
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1.1 Intermolecular versus intramolecular

CHn CHn
CHn CHn CHn
CHn
N C O H N
H

C O
L IG A N D

Intermolecular versus intramolecular hydrogen bonds.

Energetic contribution to binding comparable.
Desolvation cost for intermolecular bond may be higher.

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Dehydrons
in human hemoglobin, From PNAS
100: 6446-6451 (2003) Ariel Fernandez,
Jozsef Kardos, L. Ridgway Scott, Yuji Goto,
and R. Stephen Berry. Structural defects and
the diagnosis of amyloidogenic propensity.

Well-wrapped
hydrogen bonds are
grey, and dehydrons are green.
The standard ribbon model
of “structure” lacks indicators
of electronic environment.

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1.2 Stickiness of dehydrons

Attractive force of dehydrons predicted and measured in

Ariel Fernandez and L. Ridgway Scott. Adherence of packing defects in soluble
proteins. Phys. Rev. Lett. 2003 91:18102(4)

by considering rates of adhesion to phospholipid (DLPC) bilayer.

Deformation of phospholipid bilayer by dehydrons measured in
Ariel Fernandez and L. Ridgway Scott. Under-wrapped soluble proteins as signals
triggering membrane morphology. Journal of Chemical Physics 119(13),
6911-6915 (2003).
Single molecule measurement of dehydronic force in
Ariel Fernandez. Direct nanoscale dehydration of hydrogen bonds. Journal of
Physics D: Applied Physics 38, 2928-2932, 2005.
Fine print: careful definition of dehydron requires assessing modification of
dielectric enviroment by test hydrophobe. That is, geometry of carbon groups
matters, although counting gets it right ≈ 90% of the time [?].

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Digital Biology: aligned backbones for two paralog kinases;
dehydrons for Chk1 are marked in green, those for Pdk1 are in red.

“Modulating drug impact by wrapping target proteins” by Ariel Fernández and L.

Ridgway Scott, Expert Opinion on Drug Discovery 2007.

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2 Conclusions, extensions and limitations

Mathematical modeling of solvation (dielectric effect) leads to

quantification of variations in hydrophobicity.
• Dehydrons play a significant role in protein-ligand binding
• Dehydron patterns discriminate otherwise similar proteins
• Dehydron analysis guiding drug design
Need to understand interactions between proteins and cell
membranes.
• proteins bind to membranes (dehydrons play a role)
• proteins translocate through membranes (implications for drug
delivery)
• experimental collaboration needed!

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3 Other math modeling examples
•

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4 Sustainable research

There is no quick fix to achieve sustainability (oxymoron)

• Math models underpin long-term understanding in science
• Why not develop both from the start?
Some suggestions for further collaboration
• IMA at University of Minnesota (2008-2009 year on Chemistry and Math.)
• Establish an IMA (Institute for Math and its Applications) in China?
• Workshop on continuum modeling of biomolecules in Beijing (Sept 2009,
http://lsec.cc.ac.cn/wcmb)
Include training in math modeling for next generation
• Course in spring 2010 in ‘greater Chicago’ area
• Joint with Dexuan Xie, UW-Milwaukee; Bob Eisenberg, Rush Medical
Center

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5 Thanks

This talk was based on joint work with Wah Chiu (Baylor College of Medicine),
Ariel Ferndandez (Rice Univ.), Andy McCammon (UCSD), Kristina Rogale
Plazonic (Princeton), Harold Scheraga (Cornell), and and at U. Chicago: Steve
Berry, Peter Brune, Chris Fraser, and Matt Knepley.
We are grateful to the

• Institute for Biophysical Dynamics at the University of Chicago

• IMA at University of Minnesota (2008-2009 year on Chemistry and Math.)

• National Science Foundation: DMS Mathematical Biology

for generous support of this research.
We are also grateful to the developers of the PDB, Viper, DIP, and other biological
data bases.

Thanks for the chance to visit China again.

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