Molecular Dynamics – Molecular Dynamics Applications

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Molecular Dynamics – Molecular Dynamics Applications

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MolecularDynamicsTalk

Slides for the a talk on molecular dynamics that will be given during the 2013 UCSF iPQB bootcamp.

On Github kalekundert / MolecularDynamicsTalk

Molecular Dynamics

Sara Calhoun — Sali Lab Kale Kundert — Kortemme Lab Diego Garrido Ruiz — Jacobson Lab

You take the blue pill — The story ends, you wake up in your bed and believe whatever you want to believe. You take the red pill — You stay in Wonderland and I show you how deep the turtle-hole goes.

What is Molecular Dynamics?

Source: Bert de Groot Lab Group

How does Molecular Dynamics Work?

What Happens in a Time Step

  • Treat every atom as a classical particle.
  • Acceleration is assumed to be constant.
  • This is only true when the timestep is faster than the fastest motion occurring in the protein: bond vibrations.
A potential energy function is used to calculate the acceleration of each atom at each timestep.

How does Molecular Dynamics Work?

Bonded Forces

  • Bond Lengths:
  • Bond Angles:
  • Torsion Angles:

How does Molecular Dynamics Work?

Non-Bonded Forces

  • Van der Waals Forces
  • Electrostatic Forces:

How does Molecular Dynamics Work?

The Hydrophobic Effect

Many folding and packing interactions are mediated by the hydrophobic effect. How is it represented?

Explicit Solvent
  • Simulate every water molecule.
  • Periodic boundary conditions.
  • More expensive, but also more rigorous.

Implicit Solvent
  • Use the solvent-accessible surface area to roughly approximate the hydrophobic effect.

How does Molecular Dynamics Work?

Free Energies

  • Will one protein bind to another?
  • What conformations exist in solution?
  • How will a protein fold?
<<<<<<< HEAD

Molecular Dynamics Applications

"Turtle, I've got a feeling we're not in Kansas anymore."

How MD Addresses biophysical questions?

  • Does the data address the question?
  • Time-scales of motion
  • Appropriate assumptions

Source: Zwier and Chong, Current Opinion in Pharmacology, 2010

What is Molecular Dynamics Used For?

Observing protein motion at the atomic level

Native state dynamics - ensemble of conformational states that a molecule explores in equilibrium
Source: Graham Johnson's Youtube Channel

Understanding experimental data

Recall: Experimentally-derived structures are models
Molecular dynamics (and other sampling methods) are often used in structure determination in the refinement stage
Source: Viral RNA from UCSF Chimera Gallery - Du et al., Biochemistry 2004.

What is Molecular Dynamics Used For?

Simulating dynamic processes

Interesting biology involves dynamics processes:
  • folding
  • binding and assembly
  • catalysis
  • transport

What is Molecular Dynamics Used For?

Example: protein folds over six microseconds

Ultrafast folding of villin headpiece
Source: Freddolino et al. Biophysical Journal, 2009.

What is Molecular Dynamics Used For?

Example: observing a conformational change

EGF Receptor following ligand disassociation
Source: Arkhipov et al. Cell, 2013.

What is Molecular Dynamics Used For?

Example: water molecule through aquaporin

Source: Bert de Groot Lab Group

MD Applications at UCSF

"Turtle phone home."

MD at UCSF

Multiscale modeling of microtubule assembly

Monica Tremont-Hsu
Tubulin exists in 2 conformations: straight and bent

MD at UCSF

Multiscale modeling of microtubule assembly

Monica Tremont-Hsu
Investigate free energy landscape of tubulin using MD simulations to elucidate implications for models of assembly

MD at UCSF

Detection of cryptic binding sites on protein surfaces

Peter Cimermancic
Pocket formation involves large-scale structural reorganization that would need long traditional MD simulations to observe.

Source: Bowman and Geissler, PNAS, 2012

MD at UCSF

Detection of cryptic binding sites on protein surfaces

Peter Cimermancic
Coarse-grained force field based on inter-residue distances. Machine learning algorithm integrates data from MD as well as other features to predict cryptic binding sites

Want to learn more?

  • Take these fall quarter courses: Macromolecular Interactions and Statistical Mechanics
  • Look out for mini-courses in the spring — Matt Jacobson usually teaches a 3-week course on computational methods
  • Labs at UCSF
    • Jacobson Lab
    • Sali Lab
    • DeGrado Lab
Hasta la vista, Turtle.