Simulation Studies of Simulation Studies of Biomolecules @ Soft Biomolecules @ Soft Interfaces : Interfaces : Continuing challenge of Continuing challenge of bridging length- & bridging length- & time-scales time-scales Third Computational Chemistry Conference Third Computational Chemistry Conference on “use of computational techniques in on “use of computational techniques in chemistry, biology, biochemistry, and chemistry, biology, biochemistry, and materials science” materials science” SURA NCSA UoK ARL www.2003 SURA NCSA UoK ARL www.2003
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Simulation Studies of Biomolecules @ Soft Interfaces : Continuing challenge of bridging length- & time-scales Third Computational Chemistry Conference.
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Continuing challenge of Continuing challenge of bridging length- & bridging length- &
time-scalestime-scales
Third Computational Chemistry Conference on “use of Third Computational Chemistry Conference on “use of computational techniques in chemistry, biology, computational techniques in chemistry, biology,
biochemistry, and materials science” biochemistry, and materials science” SURA NCSA UoK ARL www.2003SURA NCSA UoK ARL www.2003
It gives me great pleasure to talk to you today about research going on in my group at UPenn that is focused on membranes and membrane-bound species.
* DISCLAIMER - This talk contains no equations – theoreticians may find the extensive use of color images offensive
My early computations dealt with ATOMIC systems. But, in the mid-1970’s, computers became more powerful I shifted to MOLECULAR solids & liquids.
Since the 1980’s my research has dealt with simulation algorithms and applications ranging from materials to bio-membranes.
Current interests - ab initio based (DFT) methods for chemical & enzyme reactions and coarse-grain simulations of self-assembling soft matter systems.
In the 1960’s COMPUTATION started to become respectable….
PROLOGUEPROLOGUE
Use computer to follow the motion of a Use computer to follow the motion of a system of atoms or molecules using system of atoms or molecules using principles of physics (Newton, Lagrange, principles of physics (Newton, Lagrange, Feynman) and statistical mechanics Feynman) and statistical mechanics (Onsager, Kubo, van Hove) to go from (Onsager, Kubo, van Hove) to go from trajectories to observables. trajectories to observables.
Interactions can be from empirical Interactions can be from empirical potentials or from quantum mechanics, potentials or from quantum mechanics, often via DFT - Car-Parrinello often via DFT - Car-Parrinello methodology.methodology.
Carlos Lopez, Steve Nielsen, Carlos Lopez, Steve Nielsen,
Preston Moore, Robert Doerksen,Preston Moore, Robert Doerksen,
Srinivas Goundla,Srinivas Goundla,
Rosalind Allen, Bin Chen, Rosalind Allen, Bin Chen,
John & Mee ShelleyJohn & Mee Shelley
* * Bridging from atoms to the Bridging from atoms to the mesoscalemesoscale
Infection Pathway of a Virus in a Living Infection Pathway of a Virus in a Living Cell*Cell*
Single-molecule real-time visualization of the infection pathway of single viruses in living cells, each labeled with only one fluorescent dye molecule.
Trajectories show various modes of motion of adeno-associated viruses (AAV) during their infection pathway into living HeLa cells:
(i) Consecutive virus touching at the cell surface and fast endocytosis;
(ii) Free and anomalous diffusion of the endosome and the virus in the cytoplasm and the nucleus; and
(iii) Directed motion by motor proteins in the cytoplasm and in nuclear tubular structures.
*Cell membranes are complex, containing lipids, proteins, cholesterol, carbohydrates, plus actin filements, etc… Design principles for Nature’s devices, plus their self- & supramolecular assembly can yield new materials.
Membranes – A Playground for Membranes – A Playground for
Nothing amuses more harmlessly than Nothing amuses more harmlessly than computation, and nothing is oftener computation, and nothing is oftener applicable to real business and speculative applicable to real business and speculative inquiry.inquiry.
A thousand stories which the ignorant tell and A thousand stories which the ignorant tell and believe die away at once when the computist believe die away at once when the computist takes them in his grip.takes them in his grip.
Samuel JohnsonSamuel Johnson: 1709-1784: 1709-1784
Protein Helix BundleProtein Helix Bundle Coarse Grain TubeCoarse Grain Tube
Hydro - philic
Pore diameter sized to accommodate “water”
Hydro-phobic
Insertion into MembraneInsertion into Membrane
Start outside the membrane (water not shown)
Tube inserts into the membrane, favoring hydrophobic interactions
Insertion into MembraneInsertion into Membrane
Tube drags lipids into the middle of the bilayer. Then “sees” the other side of the membrane.
Tube straightens up and then remains in this position through the run.
Nature’s DesignNature’s Design
CG tube in CG tube in DMPCDMPC:
“Water” goes through tube
NPT 30°C, 1atm
PoreationSnapshot of tube in CG Snapshot of tube in CG DMPCDMPC Two waters are present in the tube. Lipids removed from bottom leaflet to reveal the tube/lipid interface
Insertion into MembraneInsertion into Membrane
Antibacterial Peptide Molecules
Common traits of AB peptides:Common traits of AB peptides: Relatively short peptides.Relatively short peptides. Charged and hydrophobic groups segregate Charged and hydrophobic groups segregate
onto opposite sides of a structure.onto opposite sides of a structure. Believed to kill cells by disrupting Believed to kill cells by disrupting
membranes.membranes.
Q: De novo design of biomimetic antimicrobial molecules?
Nothing amuses more harmlessly than Nothing amuses more harmlessly than computation, and nothing is oftener computation, and nothing is oftener applicable to real business and speculative applicable to real business and speculative inquiry.inquiry.
A thousand stories which the ignorant tell and A thousand stories which the ignorant tell and believe die away at once when the computist believe die away at once when the computist takes them in his grip.takes them in his grip.
Samuel JohnsonSamuel Johnson: 1709-1784: 1709-1784