Jerome Baudry

1
MOLECULAR POLKA Complex Behavior of Small
Molecular Rotors in Material and Biological
Systems
Jerome Baudry Research Assistant Professor School
of Chemical Sciences University of Illinois at
Urbana-Champaign
Understanding Complex Systems 2007
2
Methyl group small(est) functional group in
organic chemistry
R-----CH3
C
TOP
SIDE
H
structural simplicity clear relationship
structure ? energetics Butcomplex system
because non-linear effect of environment dynamic
complexity functional complexity
3
METHYLS (VERY) SMALL BUT FUNCTIONALLY VERY
IMPORTANT
Methyl groups probes of protein dynamics and
ligand binding
Calmomdulin/peptide cmplx. CH3 rotation ?
entropy ? enthalpy? Lee et al., Nature Struct.
Biol. 2001
Methyl groups dynamics buffers mutations in HIV
protease retroviral proteins. Ishima et al, JMB
2001
CH3 mobility ? around ligand, and ? away,
Entropic compensation of ligand binding Finerty,
J. Bio. Mol. 2002
Clearly, it is the (methyl groups) that report
on the proteins () dynamic behavior (Lee et
al., Nature Struct. Biol. 2001)
4
METHYL MOLECULAR ROTORS (VERY) SMALL, BUT
FUNCTIONALLY VERY IMPORTANT
Methyl groups as micro-environmental probes
Methyl rotations as probes of peptide
dynamics Baudry et al. , J. Mol. Struct. Dyn.
1997, 49
methyl rotations as probes of polymer
structure Alvarez et al. , Macromolecules. 2000,
33
Methyl rotations coupled to proton
transfer Ushiyama et al., Angewandte Chemie, 2004
E
Methyl rotational barrier
H
H
barrier of rotation
H
structure (dihedral angle)
Clear, well-characterized relationship between
methyls (dihedral) angle and barrier
5
Methyl Rotational barriers in alanine dipeptide
crystal
Alanine dipeptide small organic molecule / model
for peptide/proteins
CH3
H
O
c
Y
F
CH3
N
Ca
C
CH3
C
N
H
O
H
2 molecules/asymmetric unit 6 different methyl
groups in asymmetric unit 5 methyls barriers ?
in crystal
6
SIDE-CHAIN (c) METHYL ROTATIONAL BARRIERS IN
ALANINE DIPEPTIDE CRYSTAL
Energy cost To rotate CH3 (kcal/mol)
quantum physics
classical physics
Crystal increased barriers
Crystal REDUCED BARRIERS !!!
adding order/packing around structure leads to
more flexibility !!
Baudry Smith, J. Phys. Chem. B. 2005,
7
Adding order/packing around structure leads to
more flexibility !!
MORE MOBILE
LESS MOBILE
gtgt
8
Barrier-reducing environment is more common that
we thought
Look for similar methyl environment in protein
crystal structures
1A2N Protein 1.6 kcal/mol (isolated ALA
3kcal/mol)
1.6 kcal/mol
alanine dipeptide crystal 2.4 kcal/mol
Also Chatfield et al, Journal of Biomolecular
NMR, 2004 ALA in SNase Kitson Hagler, ALA in
crystalline cyclopeptide Biochemistry, 1988
Baudry Smith, J. Phys. Chem. B. 2005,
9
STRUCTURAL BASIS FOR BARRIER REDUCTION
Barrier (kcal/mol)
Large (order of magnitude) reduction of
rotational barrier for specific geometries
Baudry, JACS 2006
10
DYNAMICS OF METHYL-SIZED ROTATIONS
Molecular Dynamics Simulations functionalized
single wall carbon nanotubes 300K, Time series of
C-Cl3 rotations
With satellite functionalization
NO satellite functionalization
vdW-mediated catalysis of rotations Increase
density reduced barrier and accelerate rotations
Baudry, JACS 2006
11
Condensed phase and reduced barriers
CH6 ??
X-ray crystallography identifies disordered
methyl group. Low free energy barrier for
ROTATION OF disordered methyl group nonbonded
interactions in solid phase reduce rotational
barrier.
Baudry Wilson In preparation
12
Coupling of methyl dynamics lead to complex
behavior
NEUTRON SCATTERING EXPERIMENTS / CALCULATIONS
METHYL DYNAMICS
CH3 rotations
experimental
calculated
cm-1
Baudry et al. J. Mol. Struct. Dyn. 1997
13
Coupling of methyl dynamics lead to complex
behavior
Neutron scattering
Y
F
c (side-chain)
experimental
Methyl barrier  L 
Methyl barrier  XL 
Methyl barrier  XXL 
cm-1
low frequency modes coupling of f,y,c? modified
backbone dynamics upon modification of methyl
dynamics?
Baudry et al. J. Mol. Struct. Dyn. 1997
14
FUTURE PLANS How complex ?
3D mapping of catalytic and hindering regions
and use for 3D screening of PDB CSD databases
Map / search
Can we linearize again structure / energy
Build up
T-butyl DE 10 kcal/mol, Ile,Leu etc..
If you cant beat chaos, why not exploit
it? orient control rotations, ratchet-type
potentials
15
Computational Molecular Biophysics
inter-disciplinary and multi-scale approach
life science
F ma
proteins
material science
Hy Ey
methyl-sized rotors
16
CONCLUSIONS
Structural basis for modified methyl dynamics
Very simple structure and structure/energy
relationship, but Non-bonded environment Can
increase rotational barriers (hindering van der
Waals interactions, H-bonds) Can decrease
rotational barriers (catalytic van der Waals
interactions) Variations in methyl groups
dynamics linked to large-scale effects in
condensed phase and biological structures , e.g.,
ligand binding, backbone dynamics.
Acknowledgements
Jeremy Smith (UTK/ORNL) Scott Wilson (SCS, UIUC)