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http://www-home.cr.duq.edu/~evanseck/
My computational and theoretical
research program is based on the integration of
four principal areas of expertise involving molecular
dynamics simulations, quantum mechanical methodologies,
and algorithm development. Each research area
plays a critical role in our efforts to further
the scientific advances and discoveries in the
following research fields:
· Energy
Landscapes: Biomolecular Energy and Motion
· Catalysis
of Organic Reactions: Room Temperature Ionic
Liquids
· Nanotechnology:
Molecular Receptors for Binding and Reactions
Energy
Landscapes
We have made many significant advances in the
understanding of protein energy landscapes by
studying the relationship between biomolecular
motion and energy. We now have a better understanding
on how proteins use biomechanical motion to carry
out their function. Our research focuses upon
two long-standing and controversial issues involving
carbonmonoxy myoglobin (MbCO), as described below.
Carbonmonoxy myoglobin (MbCO)
(1) Origin of the MbCO Spectroscopic A States.
(see J. Am. Chem. Soc. 1999, 121, 6444-6454) Why
does the carbon monoxide (CO) ligand have three
distinct infrared bands (called A states) when
bound to myoglobin? Are there particular MbCO
conformations that induce ligand distortion? The
role of the protein matrix in determining the
A states has perplexed scientists ever since the
crystal structure of MbCO was solved. Interpretations
of the experimental data have been controversial,
and none have simultaneously accounted for all
of the available structural, spectroscopic and
kinetic data. We have addressed this problem by
developing a novel structure-function model from
multiple molecular dynamics simulations. The new
model involves a combination of two specific and
simple side chain movements. Consistent with crystallographic
and spectroscopic data, we find that the geometric
positioning of His64 with respect to the hydrophobic
pocket defines the open (A0) and closed (A1-3)
states. In addition, we have shown that the A1,2
state is induced by a hydrogen bond between His64
and the CO ligand, and the A3 state results from
an additional electrostatic interaction with Arg45.
This is in agreement with the recent experimental
evidence for hydrogen bond formation between His64
and CO. For the first time, our proposed mechanism
is consistent with previously reported time scale
determinations of A state interconversions. Our
novel structure-function model supports the idea
that the origin of the MbCO spectroscopic A states
is determined by the fluctuating electrostatic
field generated by the cooperative motion of the
His64 and Arg45 residues.
(2) Hierarchical Tier
Model of Protein Dynamics. (see J. Am. Chem. Soc.
2000, 122, 8700-8711) After photolysis, how does
the CO ligand migrate from the heme binding site
to the solvent? Are there simple localized residue
motions or conformational equilibrium fluctuations
that govern the release and delivery of the CO
ligand? Currently, interpretations of the experimental
and theoretical data are inconclusive and subject
to considerable debate. We have studied this issue
by using a novel computational method, known as
conformational flooding (CF). The CF method extends
beyond the nanosecond time scale of traditional
molecular dynamics simulations. Within the A0
state hierarchy, three flexible regions are computed
to be responsible for conformational transitions
on long time scales. The three principal motions
are comprised of a distal pocket gate defined
by the C and D helices and interconnecting CD
loop, proximal pocket lever involving the F helix
and surrounding EF and FG loops, and hydrophobic
pocket expansion composed of the EF and GH loops
and H helix. For the first time, the ligand diffusion
mechanism is found to be a combination of distal
His64 motion (connected to A states) and equilibrium
fluctuations of the protein matrix. Thus, a unified
model that uses single residue motion (His64 through
the A0 state), and cooperative equilibrium fluctuations
(three principal conformational transitions) is
found to rationalize the most significant ligand
dissociation pathways in MbCO.
Catalysis
of Organic Reactions
To understand how to control
the rate and stereoselectivity of complex enzymatic
reactions, we have focused on how external factors,
such as protein matrix elements, solvent or Lewis
acids, could impact the structure, rate and selectivity
of simple organic transformations.
Cyclopentadiene and methylacrylate Diels-Alder
transition structure in an ionic liquid
Our principal contributions to the field of catalysis
involve the understanding of how ionic media (alkali
and alkaline earth cations) and the aqueous phase
can impact the rate and selectivity of electrocyclizations
and cycloadditions.
(3) Aqueous Catalysis
of the Diels-Alder Reaction. (see J. Am. Chem.
Soc. 2000, 122, 10418-10427) The catalytic and
endo/exo selective influence of aqueous media
on the Diels-Alder reactions are controversial
issues that continue to be intensely studied by
many research groups. The four stereospecific
transition structures of the butadiene and acrolein
Diels-Alder reaction have been studied using the
Becke three parameter density functional theory
with the 6-31G(d) basis set. The full aqueous
acceleration and enhanced endo/exo selectivity
observed by experiment is computed only when solvation
forces are approximated by the discrete-continuum
model. Consistent with previous ideas, two explicit
waters are used to satisfy localized hydrogen
bonding of acrolein and induce a charge polarization
of the endo s-cis transition structure. Approximately
50% of the rate acceleration is attributed to
hydrogen bonding, and the remainder to bulk phase
effects which includes ca. 10% enforced hydrophobic
interaction. The computed endo preference is enhanced
to 2.4 kcal/mol in aqueous solution, in agreement
with experiment. The catalytic and endo/exo selectivity
results are consistent with the hypothesis of
maximum accumulation of unsaturation.
(4) Ionic Liquid Effects
on the Diels-Alder Reaction. Due to the importance
of the Diels-Alder reaction in organic synthesis,
several physical and chemical methods have been
invoked to accelerate its rate and control its
stereoselectivity. Recently, neutral ionic liquids,
such as 1-butyl-3-methylimidazolium have been
used as an environmentally safe and recyclable
alternative to conventional catalytic methods.
The molecular origin of how ionic liquids influence
the well-known Diels-Alder reaction is a matter
of controversy. Current views on how ionic liquids
induce their catalytic effect are thought to involve
high internal pressure, Lewis acid catalysis,
or a combination of both. Other physical forces
and effects have been recently suggested. The
goal is to provide physical insight into the molecular
origin of catalysis and stereoselectivity caused
by ionic liquids to design new catalytic materials
for other pericyclic reactions, such as aldols,
enes, sigmatropic shifts and cycloadditions.
Nanotechnology
We have completed several
joint experimental and theoretical investigations
of intermolecular complexation on different molecular
receptors (cyclophanes, cyclodextrins, and calixarenes).
The goal is to better understand the intermolecular
bond and control its complementary and cooperative
nature.
Electrostatic Potential of the Blue-Box Molecular
Receptor
Our primary contributions to the understanding
of supramolecular phenomena involves (1) defining
the important nonbond interactions in inclusion
complexes involving cyclobis(paraquat-p-phenylene),
14+, with substituted 1,4-phenyl and 4,4'-biphenyl
guests, (2) the effects of extending the ethyleneoxy
sidearms of the guests to mimic rotaxanes, shuttles,
and switches, and (3) systematic changes to 14+
to create a novel molecular receptor, 24+, with
new guest binding properties. We are currently
expanding our efforts to understand a wider range
of receptors (cyclodextrins, calixarenes, and
derivatives).
(5) Cyclophane Cavity Forces. (see J. Phys. Org.
Chem. 1997, 10, 369-382 and J. Am. Chem. Soc.
1996, 118, 10257-10268) We have shown that inclusion
complex formation and stability is primarily determined
by the combination of two main nonbond interactions
involving aromatic stacking of the guest within
the 14+ cyclophane cavity. It was determined that
the primary basis for the molecular recognition
between 1,4-substituted phenyl guests and 14+
is short-range stabilizing electrostatic forces.
In contrast, the recognition force between 4,4'-substituted
biphenyl guests and 14+ was dominated by polarizability.
Therefore, the balance between molecular polarizability
and electrostatics controls the differential binding
affinity and structural recognition with 14+.
(6) Cyclophane External
Forces. (see J. Org. Chem. 1996, 7298-7303) We
have shown that external interactions between
guest ethyleneoxy sidearms and the exterior of
the cyclophane are significant in inclusion complex
formation. The binding constants with 14+ have
been determined by UV-VIS spectrophotometry (in
CH3CN) for a series of p-phenylene guests, symmetrically
substituted with sidearms of varying length and
functionality. Semiempirical molecular orbital
theory was employed to provide a detailed structural
and energetic interpretation of the experimental
binding data. The length of the sidearms as well
as the type and position of the heteroatoms on
the sidearms were systematically varied in order
to understand the effects of external interactions
on the association constants of the guests with
host 14+.
(7) Cyclophane Modification
and Creation. (see J. Org. Chem. 2000, 65, 2083-2089)
To probe the ideas of nontraditional nonbond interactions,
a new tetracationic molecular receptor has been
synthesized and studied by semiempirical MO theory.
This novel macrocycle, 24+, derived from pentacyclo[5.0.0.02,6.03,10.05,9]
undecane-8,11-dione (PCU-8,11-dione), structurally
resembles cyclobis(paraquat-p-phenylene), 14+,
in which a xylyl group has been replaced by a
PCU unit. This derivatization effectively increases
the size and flexibility of 24+ and changes its
electronic, dynamical and binding properties.
A conformational search using Osawa's corner flapping
technique and the PM3 semiempirical method identified
eight unique and low energy 24+ conformers. The
principal regions of structural variation occurred
in the bipyridinium torsion and in the ethylene
bridges between PCU and the tetracationic unit.
The inclusion complexes of 14+ with 1,4-disubstituted
benzenes and 4,4'-disubstituted biphenyls have
been studied by PM3. The first solvation shell
was approximated by twelve acetonitriles. Binding
of 1,4-disubstituted benzenes and 4,4'-biphenol
is shifted from the 24+ center. In all computed
complexes, 24+ binds stronger than 14+. Important
in molecular devices, host 24+ has enhanced binding
preference for benzidene over 4,4'-biphenol, as
compared to 14+. These properties can be exploited
in the future design of supramolecular systems
with potential applications as nanoscale devices.
Recent Publications
"Density Functional
Theory Study of the Aqueous Phase Rate Acceleration
and Endo/Exo Selectivity of the Butadiene and
Acrolein Diels-Alder Reaction" Kong, S.;
Evanseck, J. D. J. Am. Chem. Soc. 2000, 122, 10418-10427.
"Functional Significance
of Hierarchical Carbonmonoxy Myoglobin: Conformational
Substates and Transitions by Conformational Flooding
Simulations" Schulze, B. G.; Grubmüller,
H.; Evanseck, J. D. J. Am. Chem. Soc. 2000, 122,
8700-8711.
"Synthesis and Inclusion
Complexation Studies of a Novel and Selective
Molecular Receptor for 1,4-Disubstituted Benzenes
and 4,4'-Disubstituted Biphenyls" Macias,
A. T.; Kumar, K. A.; Marchand, A. P.; Evanseck,
J. D. J. Org. Chem. 2000, 65, 2083-2089.
"Cooperative Role
of Arg45 and His64 in the Spectroscopic A3 State
of Carbonmonoxy Myoglobin: Molecular Dynamics
Simulation, Multivariate Analysis and Quantum
Mechanical Computations" Schulze, B. G.;
Evanseck, J. D. J. Am. Chem. Soc. 1999, 121, 6444-6454.
"Locally Accessible
Conformations of Proteins: Multiple Molecular
Dynamics Simulations of Crambin" Caves, L.
S. D.; Evanseck, J. D.; Karplus, M. Protein Science
1998, 7, 649-666.
"Inclusion Complexation
of Cyclobis(paraquat-p-phenylene) and Related
Cyclophane Derivatives with Subsitituted Aromatics:
Cooperative Non-Covalent Cavity and External Interactions"
Castro, R.; Davidov, P.; Evanseck, J. D.; Kaifer,
A. E. J. Phys. Org. Chem. 1997, 10, 369-382.
"The Effect of Sidearm
Length and Functionality of p-Substituted Phenyl
Derivatives on the Binding with Cyclobis(paraquat-p-phenylene)"
Castro, R.; Nixon, K. R.; Evanseck, J. D.; Kaifer,
A. E. J. Org. Chem. 1996, 7298-7303.
"The Unexpected Roles
of Host Solvation and Guest Polarizability and
Maximum Hardness in Supramolecular Inclusion Complexes:
A Dual Theoretical and Experimental Study"
Castro, R.; Berardi, M. J.; Córdova, E.;
Ochoa de Olza, M.; Kaifer, A. E.; Evanseck, J.
D. J. Am. Chem. Soc. 1996, 118, 10257-10268.
Office Phone:(412) 396-6337
Email: evanseck@duq.edu |
