Nsf China, L. Ridgway Scott

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. 1

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Ligand binding removes water: dehydrons CHn

CHn CHn

CHn C

O

H

H

CHn C

N

O

CHn 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! 2

N

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Intermolecular versus intramolecular CHn

CHn CHn

CHn

H

C

CHn C

N

O

O

CHn H

N

L IG A N D

Intermolecular versus intramolecular hydrogen bonds. Energetic contribution to binding comparable. Desolvation cost for intermolecular bond may be higher. 3

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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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 [?]. 5

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 Fern´andez and L. Ridgway Scott, Expert Opinion on Drug Discovery 2007. 6

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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! 7

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Other math modeling examples •

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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 9

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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. 10