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PAST GRADUATE STUDENTS Dr. Stephen Habay, Ph.D. program. Graduated 2006 Dr. Christopher Levins, Ph.D. program. Graduated 2006Dr. Gregory Bird, Ph.D. program. Graduated 2006 Dr. Paul Morgan, Ph.D. program. Graduated 2007Megan Macala, M.Sc. program. Graduated 2007Chris Morgan, M.Sc. program. Graduated 2007Laura Belasco, M.Sc. program. Graduated 2007Dr. Sharad Gupta, Ph.D. program. Graduated 2009Dr. Zachary Brown, Ph.D. program. Graduated 2010Dr. Qingquan Zhao, Ph.D. program. Graduated 2014Dr. Matthew Parker, Ph.D. program. Graduated 2015Dr. Mahboubeh Kheirabadi, Ph.D. program Graduated 2015
CURRENT GRADUATE STUDENTS Kavitha Akula, Ph.D. program. Senzhi Zhao, Ph.D. Program. Chongsong Xu, Ph.D. Program. Conrad Pfeffer, Ph.D. Program.J.D. Northrup, Ph.D. Program.Jae Eun Cheong, Ph.D. Program.Yanfeng Fan, Ph.D. Program.Steven Fletcher, Ph.D. Program.Melody Pham, Ph.D. Program
COLLABORATORS Prof. Mark Feitelson (Temple, Biology) Dr. Alla Arzumanyan (Temple, Biology) Prof. Ken Houk (UCLA)
FUNDING
National Institute of Health, NIGMSNational Science Foundation
Defense Threat Reduction Agency (DOD-DTRA) - Dr. Ilya ElashviliTemple University
Schafmeister Group Abiotic Biological Chemistry -‐ ABC Nanometer scale -‐ Angstrom precision
Molecular Building Blocks amenable to Computational Design
• Spiroligomers - synthetic alternative to proteins • Built from rigid, cyclic, functionalized building blocks
2
New synthetic developments enable spiroligomer nanostructure synthesis
New synthetic developments enable spiroligomer nanostructure synthesis
Red nitrogens are 15N labeled for Structure Determination
5
A transesterifica8on catalyst
Kheirabadi, M., Çelebi-Ölçüm, N., Parker, M. F. L., Zhao, Q., Kiss, G., Houk, K. N., and Schafmeister, C. E., JACS 134, (2012): 18345–18353. doi:10.1021/ja3069648,
New synthetic developments enable spiroligomer nanostructure synthesis
8One of 224 x 509 = 3.3x1022 possible structures
O
(S)(S)N
(R)(R)
N(S)(S)
N
(S)(S) N
(S)(S)N
(S)(S)N
(S)(S)
N(S)(S)
N
(S)(S)
N(S)(S)
N
(S)(S)N
(S)(S)N
(S)(S)
OHN N
(S)(S)
(S)(S)
N (S)(S)
N
(S)(S)
N(S)(S)
N
(S)(S)N
(S)(S) N
(R)(R)NH OO
HN
O
O
NH
O
(S)(S)N
(S)(S) N
(S)(S)
ONH
NH2
HN
O
O
O
O
OO
O
O
OO
H2N
O
O
O
O O
NH2O
OO
O
O
OO
NH2
N
N
NH
O
O
O
O
O
HN
ON
Exact Mass: 2846.15
21.3
-5
45
95
145
195
245
295
0 5 10 15 20 25 30
Abs
orba
nce
(mA
u)
Retention Time (min)
HPLC of Fun_3XBun Closed @ 274
1,424.1
-0.05
0.45
0.95
1.45
1.95
2.45
2.95
3.45
3.95
4.45
4.95
1400 1420 1440 1460 1480 1500
Abu
ndan
ce
Mass (amu)
MS of Fun_3XBun Closed
(M+2)/2
How can we design macromolecules that do things?
Monte Carlooptimization
Mutatemolecule
BuildstructureScore
structure
Startingmolecule
Specialized software with tightly coupled functions
in the same processor
Requires a FAST, chemistry-aware, programming language
CANDO: fast native code for macromolecular design
LLVM-IR(Apple, Google)
Monte CarlocodeMutate
molecule
BuildstructureScore
structure
Startingmolecule
Fast native coderuns on
100,000’s CPUs- currently
1/4 speed of C
;;;;;; Build starting geometry for all 32 stereoisomers;;;(dotimes (i 32) (set-stereoisomer *stereocenters* i :show t) (build-good-geometry-from-random *agg* *ff*) (save-mol2 *agg* (indexed-pathname #P"fuzi/run.mol2" i)))
(array-stereoisomers #P"fuzi/run.mol2" 32)
;;; 32 stereoisomers are written into fuzi/run000.mol2;;; … fuzi/run031.mol2
Wong, K. and Gao, J. Biochemistry 2007, 46, 13352-13369.
“Molecular Metaprogramming” software that designs molecules
~ 3 nanometers
Organophosphate hydrolase
14
~ 2 nm
~ 2 n
m~ 2
nm
~ 2 nm
~ 6 nm
~ 4
nm
Functionalized Multi-spiroligomersare programmable, atomically precise “Bricks”
15
(1) Reversible Covalent “Dock and Lock”
Many copies of product
16
(2) LB assembly of atomically precise 2D arrays
Selective ion and water channels
Top view
18
NN
NM+
NN
N
EDTA
M+
NN
N
NN
N
(3) 3D Printing of Atomically Precise Nanostructures
19
Zn
Mn
dx.doi.org/10.1021/ic4003498 | Inorg. Chem. 2013, 52, 6457−6463
20
M+
3D Printing of Atomically Precise Nanostructures
+ EDTA- M+
3D Printing of Atomically Precise Nanostructures
Could be parallelizedusing (2) LB 2D array
Release!
…
Diverse, rigid cores
Pairs ofbonding groups
Diversefunctional groups
NBoc CO2t-Bu
HNHO2C R1
NBoc CO2t-Bu
HNHO2C R2
NBoc
CO2t-Bu
HNHO2C
NBoc
CO2t-Bu
HN
HO2C
R3
R4
NCO2H
NON
N
O
ON
N
O
O
R2
R3
R4 NO
R5
NHP
R1
Pairs ofbondsconnectrigidbuildingblockswhichtogetherdirectfunctionalgroups
A B
Hardware: Spiroligomers
CANDO
C++ LLVM-IR
Design Software: CANDOMonte Carlo Mutate
molecule
BuildstructureScore
structure
Startingmolecule
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