(Salen)Mn(III) Compound as a Nonpeptidyl mimic of (Salen)Mn(III) Compound as a Nonpeptidyl mimic of CatalaseCatalase
Catalase2H2O2 2H2O + O2
N
O
N
O
Mn
RR
X X
Y Y
Cl
An incomplete list of possible treatment applications:Alzheimer’s diseaseStrokeHeart diseaseAgingCancer (reduction of the side effects, allowing higher drug doses to be administered)
Substituents change enzymatic activity:Substituents change enzymatic activity:the biomimetic can be tuned structurally and electronically the biomimetic can be tuned structurally and electronically
Intelligent design of Biomimetics (Synzymes):Intelligent design of Biomimetics (Synzymes):
RASGAP
GTP
~ 40 ÅQM part: 45 atoms MM part: 1608 atomscollected in 483 EFs
2.0
2.5
3.0
3.5
02468
10121416182022242628303234
1.82.0
2.22.4
2.62.8
3.0 3.2 3.4 3.63.8
Potential energy surface for the GTP hydrolysis for the RAS/GAP complex model (calculated at the B3LYP/4-31G*/3-21G level)
E(k
cal/
mo
l)
R[O(W)-P]
R[P-O(P)]
Reactionpath
Characterization of Ping-Pong Mechanism for Characterization of Ping-Pong Mechanism for Dismutation of HDismutation of H22OO22 MoleculeMolecule by (Salen)Mn(III)by (Salen)Mn(III)
Mechanism-Based Structural Tuning of Catalase Activity Mechanism-Based Structural Tuning of Catalase Activity of Salen-Manganese Complexes for R=OMe substituted of Salen-Manganese Complexes for R=OMe substituted
compoundcompound
Abashkin, Burt Inorg. Chem., 2005; Abashkin, Burt Phys. Chem. B, 2004
Estimated computer resources needed for the exhaustive tuning :
50-60 (substituted biomimetics) x 200-400 (hours of large CPU) = YEARS
Dramatic increase in computation power is needed to solve the problem
Dramatic increase in computation power is needed to solve the problem
Computational assistance in developing Computational assistance in developing novel biological nanodevices:novel biological nanodevices:
Target
DNA/RNA Target
“Simple” Nanoprobe for detecting biowarfare reagents and genetic diseases.
Red light
FluoresceinGreen Light
Recognizer Recognizer
Practical development of Nanoprobe needs optimization of various elements:Practical development of Nanoprobe needs optimization of various elements:
Target
Rod
Polyethylenglycol (PEG) tether
Recognizer Recognizer
Linker
Fluorophores
Computational support includes QM ( hundreds of atoms) and MM (thousands of atoms) calculations and/or complex
QM/MM simulations
Computational support includes QM ( hundreds of atoms) and MM (thousands of atoms) calculations and/or complex
QM/MM simulations
Feasible only on a supercomputer
Epidermal Growth Factor Receptor Pathway
Dendrimers
Dendrimers
Large number of micro-environments with different properties
Gold Nanoparticles
Gold Nanoparticles
Buckyball (left)500 atoms3000 electrons
Gold Particle3000 to 30000 atoms500,000 electrons
Problem grows as Ne2