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