Deriving Fundamental Laws of Viral Behavior from Principles of Molecular Physics: Nanoprobes and Mul

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Deriving Fundamental Laws of Viral Behavior from
Principles of Molecular Physics Nanoprobes and
Multiscale Analysis
Peter J. Ortoleva Center for Cell and Virus
Theory Department of Chemistry, Indiana
University Bloomington IN 47405 ortoleva_at_indiana.e
du [phone] sysbio.indiana.edu
Center for Cell and Virus Theory ?
http//sysbio.indiana.edu ? ortoleva_at_indiana.edu
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CCVT Members

• Steve Corenflos - System Administrator, Software
  Developer
• Lisa Ensman - Web and Database Designer
• Jianmiao Fan - Graduate Student, Chemistry
• Margaret Jensen - Editorial Specialist
• Yinglong Miao - Graduate Student, Chemistry
• Peter Ortoleva Director CCVT, Distinguished
  Professor
• Christi Perkins Undergraduate Research Student
• Kun Qu - Graduate Student, Chemistry
• Zeina Shreif - Graduate Student, Chemistry
• Ana Yesnik - Undergraduate Research Student

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Collaborators and Advisors

• R. Bashir, Purdue University
• J. Johnson, Scripps
• M. Fontus, Prairie View AM University
• N. Kelley-Loughnane, AFRL
• T. Keyes, Boston University
• R. Kuhn, Purdue University
• J. Schlager, AFRL
• M. Stone, AFRL
• L. Viveros, AFRL

Center for Cell and Virus Theory ?
http//sysbio.indiana.edu ? ortoleva_at_indiana.edu
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Outline The Multiscale perspective on

• Bionanosystems and order parameters
• Cell regulatory networks and their implications
  for cancer and stem cell behavior

Center for Cell and Virus Theory ?
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Thousands of years of observations on the heavens
summarized in Fma.
Science proceeds by big ideas and not by big
technology.
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Multiscale analysis shows Brownian motion is not
evidence of life force.
Albert Einstein (1879 -1955)
Microscope invented in 1590 by Zaccharias Janssen.
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Bionanosystems Multiscale Virology
(a)
(b)
Ribbon representation of CCMV capsid states
(derived from all-atom structures) in (a) native
and (b) swollen states
Center for Cell and Virus Theory ?
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Features of The Nanosystem

• Rapid atomic fluctuations
• Slow nanoscale dynamics
• Multiple length scales
• Multiple time scales

• Schematic nanoparticle immersed in a host medium

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Cross-Talk Across Scales in Time
The characteristic time
depends on the mass ratio and the
energy and entropy change in the process.
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Interaction Across Scales in Space
Entropy and Random Forces
Nanostructure
Atomic Scale Objects
Constraints on Ensemble of Fluctuations
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The 3000 Year Bottleneck

• NAMD (an optimized MD code)
• running on a 1,000 CPU platform yields
• 1 ns/day for a small virus
• Viral structural transitions take milliseconds or
  longer
• 3,000-year simulations needed!

Center for Cell and Virus Theory ?
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NanoX Simulator Applications

• Antiviral vaccines and drugs
• Pre-empt viral pandemics
• Nanocapsules for drug, siRNA, and gene delivery
• Nanoparticles to disable viruses and bacteria
• Medical imaging
• Nanobioconstructs for detection

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Classical Mechanical Description
The all-atom description is in positions
and momenta
Newtons Equations
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Bio OPs Emerge from Sea of Atomistic Chaos
In multiscale statistical mechanics we give up
trivial detail, relax, and make progress.
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Order Parameters

• Capture nanoscale features of interest
• Expressible in terms of the N-atom state
• Slowly varying in time
• Form a complete set of slow variables

Center for Cell and Virus Theory ?
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Coherent and Stochastic Motions
Center for Cell and Virus Theory ?
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Generalized OPs
Center for Cell and Virus Theory ?
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Liouville Equation of
Dynamics
yields evolution in time t of the probability
density ?.
Center for Cell and Virus Theory ?
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Simple Multiscale Function
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Multiscale Reformulation
Center for Cell and Virus Theory ?
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Multiscale Perturbation Scheme
W satisfies the Smoluchowski equation
Center for Cell and Virus Theory ?
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Langevin Dynamics
Center for Cell and Virus Theory ?
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Order Parameter Fluctuating Time Course
Time courses for overall smooth (left) and more
complex (right) basis function OPs
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MD/OPX Demonstration

• For a 512 processor system
• Code Run time/nanosecond
• NAMD 33 hours
• MD/OPX 5 hours

MD/OPX Simulation of swollen CCMV capsid
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Molecular Dynamics/OP extrapolation (MD/OPX)
F(td) from MD
F(t)
F(t?)
Center for Cell and Virus Theory ?
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Stem Cells and Cancer
Epithelial call regulatory network abnormalities
are being discovered in our search for origins of
cancer and stem cell diseases.
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TRN Complexity
Monocyte SEB partial network automatically
generated using our transcriptional regulatory
network discovery system and Jett/Hammamieh
microarray data (degreegt20).
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Global context
Genome-wide TRN
Subnetworks or signaling pathway
Key transcription factor