Molecular Dynamics of DNA origami nanostructures Christopher Ma ff - - PowerPoint PPT Presentation

Molecular Dynamics of DNA

• rigami nanostructures

Christopher Maffeo PI: Aleksei Aksimentiev

Department of Physics University of Illinois at Urbana-Champaign

Blue Waters Symposium

June 5, 2018

All-atom Molecular Dynamics (MD)

U = ⌥

bonded

⇧ k(rij − r0)2 + kθ(⇥ − ⇥0)2 + k(1 + cos(n⌅ + ⇤)) ⌃ + ⌥

i>j

⇧ −Umin ⇤Rmin rij ⇥12 − 2 Rmin rij ⇥6⌅ + Cqiqj 0rij ⌃

bond angle dihedral Lennard-Jones (van der Waals) electrostatic

Atoms modeled as classical point particles Interactions prescribed by CHARMM36 force field with CUFIX corrections Simulations run using NAMD† on Blue Waters

† Phillips et.al. J. Com. Chem. 26:1781

Single-stranded DNA hybridizes with sequence specificity

phosphate sugar

adenine thymine

.

cytosine guanine .

2.5 nm

DNA origami

Viral DNA (scaffold)

Building a structure with nanoscale precision by folding DNA

Synthetic DNA (staples) ~30–40 nucleotides

DNA origami structures

Dietz and coworkers, Science (2012) Dietz and coworkers, Science (2015)

A

12.5 mM MgCl2 30 mM MgCl2 5 mM MgCl 25 nm

Shih and coworkers, Science (2009) Yan and coworkers, Science (2011) Yan and coworkers, Science (2013)

Cryo-electron microscopy and all-atom simulation


for DNA origami structure prediction

RMSD of scaffold (nm) time (ns)

1 1.5 2 100 200

Reference structure docked into cryo-EM

PNAS 109:20012 Nucleic Acids Research 44:3013

Comparison between simulation and experiment

simulation EM density psuedo-atomic model

Nucleic Acids Research 44:3013

Interactions in a simple coarse-grained DNA model

100 mM

4 nm
 cutoff

Coarse-grained model captures programmed curvature

0° 180° 30° 60° 90° 120° 150°

Design and TEM: Science 325:725

Adaptive resolution simulation of DNA

• rigami systems

Andersen et al., Nature 2009

Birkedal Group

DNA-based Voltage sensing

5 nA 150 ms

Experimental setup

Idea: use DNA origami as a local voltage probe

All-atom MD simulation

ACS Nano 9:1420-1433 (2015)

Keyser Group

Design of a nanoscale voltage sensor

Keyser and Tinnefeld Groups

Nano Lett., doi: 10.1021/acs.nanolett.7b05354 (2018)

Coarse-grained simulations of a FRET plate capture

600 mV 400 mV 300 mV 200 mV 100 mV ~5 bp/bead CG model 40 µs simulations

Nano Lett., doi: 10.1021/acs.nanolett.7b05354 (2018)

CG simulation of FRET efficiency

400 mV 300 mV 200 mV 1 µs simulations 2 beads/bp CG model 100 mV

Design A1

Nano Lett., doi: 10.1021/acs.nanolett.7b05354 (2018)

Voltage sensing with DNA origami

Experiment: Simulation:

Nano Lett., doi: 10.1021/acs.nanolett.7b05354 (2018)

DNA Ion Channels

Nano Letters, 13: 2351 Porins, 1 nS conductance Jejoong Yoo

Yoo & Aksimentiev, JPCL 6, 4680 (2015)

Gramicidin ion channels Conductance < 0.1 nS

DNA Ion Channels

Keyser Group Membrane channel made of a single DNA duplex (0.1 nS)

Nano Letters 16:4665 (2016) ACS Nano 10:8207 (2016)

Porin-like DNA channel 40 nS

Chen-Yu Li

All-atom MD simulation of lipid-DNA interface

Lipid molecule around the DNA channel can translocate to the other leaflet.

No applied electric field

Chen Yu Li

http://dx.doi.org/10.1101/241166

Lipid translocation through toroidal pores is very common and very fast

DPhPC DPhPE 3-5 orders of magnitude faster than natural scramblases

Lipid translocation through toroidal pores is very common and very fast

scramblase

Experimental verification

Ohmann, Li, … Ulrich F. Keyser, Aksimentiev, http://dx.doi.org/10.1101/241166

Scale bars are 10 µm

Keyser Group

Works in human cells

Annexin V binds specifically to PS lipids found in inner leaflet of human cells

Breast cancer cells from the cell line MDA-MB-231 Positive control: apoptosis-inducing microbial alkaloid staurosporine Negative control: DNA folding buffer Scale bar is 20 µm

http://dx.doi.org/10.1101/241166

Acknowledgements

Jejoong Yoo Chen-Yu Li Aleksei Aksimentiev Victoria Birkedal Ulrich Keyser Philip Tinnefeld

Aksimentiev Group Center for Macromolecular Modeling and Bioinformatics