UTILIZING FORCE FIELD METHODS TO EXPLORE THE POTENTIAL ENERGY LANDSCAPES OF FLEXIBLE BIOMOLECULES TF10: Zachary S. Davis †, Joanne M. Carr *, Ivan Y. W. Tan *, David J. Wales *, Timothy S. Zwier † †Department of Chemistry, Purdue University, West Lafayette, Indiana *Cambridge University Center for Computational Chemistry, Lensfield Road, Cambridge, United Kingdom CB2 1EW

E XPANDING M OLECULAR H ORIZONS There are several challenges we face as we press towards larger and larger molecules: Leave behind the realm of relying on chemical intuition Increased complexity of potential energy surfaces to explore Ab initio lagging behind experiment  Need new methods 2 Valinomycin Lignin

A DVENT OF N EW T ECHNIQUES Constantly striving for methods that will allow for in-depth study of larger molecules Population Transfer Methods Laser desorption methods Electrospray ionization Effective Fragment Potential Necessary to study the potential energy landscape to gain appreciation of the complexity of larger systems 3

U SEFULNESS OF C ALCULATIONS Calculated conformations provide theoretical vibrational frequencies that can be used to assign experimental conformers 4

M ULTIPLE E XPERIMENTAL C ONFORMERS When more than one conformer is present in the jet, one or both of the following conditions arise: 1.Two or more conformers have comparable energies 2.If not, large barrier preventing population from cooling into global minimum. 5

M ULTIPLE E XPERIMENTAL C ONFORMERS As an ensemble of molecules cools in a supersonic expansion, what pathways are taken? If we see multiple conformers, what is the barrier to isomerization? 6 A B ? ?

M ULTIPLE E XPERIMENTAL C ONFORMERS To help elucidate the isomerization process, one experimental approach is population transfer spectroscopy 7 Stimulated Emission Pumping- Population Transfer Spectroscopy S0S0 S1S1 Zero-point Level C A B 5. UV Probe 4. Collisional Cooling 3. UV Dump 2. UV Pump Excited Vibrational Level B*B* 1. Initial Cooling 6. Fluorescence detection

U TILITY OF D ISCONNECTIVITY G RAPHS In either condition, it would be beneficial to be able to examine the potential energy landscape –Identify transition states and associated barriers –Identify conformational families –Identify excluded minima 8 D. J. Wales, Int. Rev. Phys. Chem., 2006, 25, 237–282; O. M. Becker, M. Karplus, J. Chem. Phys. 106, (1997) ‘palm tree’ ‘weeping willow’ ‘banyan tree’

U TILITY OF F ORCE F IELDS Benefits Easily used on large molecules, clusters, solvated species Calculations are done quickly compared to ab initio methods Relatively easy to change parameters Drawbacks All atoms of the same type have the same parameters – Bond angles, dihedrals, force constants, etc. – Different molecular environments difficult to fully duplicate Dispersive interactions are not included Energy ordering almost always differs from ab initio 9

N UDGED E LASTIC B AND M ETHOD A B 10

N UDGED E LASTIC B AND M ETHOD A B 11

N UDGED E LASTIC B AND M ETHOD A B 12

N UDGED E LASTIC B AND M ETHOD A B 13

S YNTHETIC F OLDAMERS Series of capped β-peptides –Ac-(Phe/Ala-Phe/Ala-Phe-Ala)-NHMe Number of degrees of freedom increases with number of amino acid residues Increasingly complex potential energy landscape and therefore disconnectivity diagrams 14

Β-P EPTIDES 15 C8 (red), A C6 (green), B & C

Β-P EPTIDES 16 C8, 2  1 (red) C8, 2  3 (green)

Β-P EPTIDES 17

C ARBOXYBENZYL D ERIVATIVES By introducing an aromatic N-terminal cap, non-aromatic peptides may be studied Polyglycines have been shown to adopt helices in the gas phase 18 Carboxybenzyl N-terminal Cap

Z-(G LY ) 3 -OH 19 C10/C7 Structure

Z-(G LY ) 3 -OH 20 C10/C7 Structure

Z-(G LY ) 3 -OH Ribbon Structure

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C BZ -(G LY ) 3 -OH 37 C13; cis in third amide group

C BZ -(G LY ) 5 -NHM E 38

I N C ONCLUSION Shift towards larger molecules requires a more in-depth investigation of their associated potential energy landscapes Force fields will require reinvestigation as we use them in new ways Methods offer test of available force fields Medium size regime ideal: experiment, ab initio and force fields all available 39

Zwier Group Members: Dr. Vanesa Vaquero (WG09) Dr. Ryoji Kusaka (TD09) Evan Buchanan (WG08, WF12) James Redwine Jacob Dean (TF09, WG10) Deepali Mehta (TG10) Nathan Kidwell (TG09, FB07) Joe Korn Di Zhang (FB08) Nicole Burke Joe Gord (MF08) Patrick Walsh Special Thanks: Dr. Chris Whittleston, Cambridge 40 A CKNOWLEDGEMENTS CHE