NMR Steered Sampling Conformation Sampling via MC Rotation of Dihedrals Selected from NMR Experiment - PowerPoint PPT Presentation

1 / 22
About This Presentation
Title:

NMR Steered Sampling Conformation Sampling via MC Rotation of Dihedrals Selected from NMR Experiment

Description:

Perform steered sampling to rapidly identify clusters. Base docking ensemble on these experimentally supported clusters. Our Contribution ... – PowerPoint PPT presentation

Number of Views:19
Avg rating:3.0/5.0
Slides: 23
Provided by: nd2
Category:

less

Transcript and Presenter's Notes

Title: NMR Steered Sampling Conformation Sampling via MC Rotation of Dihedrals Selected from NMR Experiment


1
NMR Steered SamplingConformation Sampling via
MC Rotation of Dihedrals Selected from NMR
Experiments
  • Paul Brenner

Jan 19th 2004
2
Motivation
  • Robust conformation sets needed
  • for effective docking
  • How to sample
  • 3N phase space?
  • Energy barriers
  • Experimental data
  • to guide sampling

3
Sampling
  • Definition
  • Our Contribution

4
Methods and Metrics
  • Propagator
  • Rotation Algorithm
  • Conformation String Generation
  • Cluster Analysis

Ubiquitin
BPTI
Butane
5
Propagator
6
Rotation
  • General Rotation
  • Determine all atoms for rotation
  • Normalize positions wrt primary axis
  • Rotate positions
  • Rotate velocities relative to the positions
  • Ring Considerations
  • Must recognize a ring condition
  • Assign rotation angles in ratio to the number of
    dihedrals in the ring

7
  • Conformation Strings
  • Selection of the dihedral set
  • Locate dihedral energy
  • maxima via Brent's Method
  • At each step assign each dihedral to its current
    well
  • Store the strings
  • Cluster Analysis
  • Assign clusters iteratively based on the
    conformation with the greatest number of
    neighbours according to RMSD qualifier

Ref Kirchhoff, Bass, Hanks, Briggs, Collet,
McCammon J. Am. Chem. Soc. 1996
Ref Daura, van Gunsteren, and Mark PROTEINS
1999
8
Evaluation - BPTI
9
Evaluation - BPTI
10
Evaluation - BPTI
11
Evaluation - Ubiquitin
12
Evaluation - Ubiquitin
13
Evaluation - Ubiquitin
14
NMR Experimental Data
  • Utilize NMR data to identify highly flexible
    backbone or side chain regions
  • Select dihedrals for rotation inline with the
    flexible regions
  • Perform steered sampling to rapidly identify
    clusters.
  • Base docking ensemble on these experimentally
    supported clusters

15
  • Our Contribution
  • La
  • La
  • La
  • Future Work
  • Utilization of this conformation ensemble vs
    those generated by peer sampling processes
  • Validation versus standard integrators (MD, HMC)
    in peer programs (Gromacs, NAMD, etc)
  • Identification of viable pathways

16
Acknowledgements
  • Special thanks to the following
  • David Salyers, Thierry Matthey,
  • and Scott Hampton
  • My advisor Dr. Jesus A. Izaguirre
  • Funding
  • This work was partially supported by
  • NSF grant award No. 0135195
  • Tools
  • Protomol, VMD, OpenOffice, GIMP, Linux

17
  • Questions

18
Evaluation - Butane
HMC
CDHMC
MD
MD
19
Conformation Strings
  • Preprocessing
  • Selection of the dihedral set
  • Initialization
  • Locate dihedral energy maxima via Brent's
  • String Identification
  • Assign each dihedral
  • to its current well
  • Store the strings

Ref Kirchhoff, Bass, Hanks, Briggs, Collet,
McCammon J. Am. Chem. Soc. 1996
20
Cluster Analysis
  • Start with the set of unique conformations
  • Calculate RMSD for each conformation pair
  • For each conformation calculate its number of
    neighbors based on a maximum RMSD value
  • Remove from the set the conformation with the
    highest number of neighbors its neighbors
  • - This subset of conformations is a cluster
  • Iterate through steps 3 and 4 until the primary
    set is empty

Ref Daura, van Gunsteren, and Mark PROTEINS
1999
21
Simulation Parameters
  • Temperature 500K
  • Normal Boundary Conditions (not periodic)
  • 20MD steps per HMC step
  • MD
  • LeapFrog Integrator
  • 0.5 Femtosecond Timestep
  • Bond, Angle, Dihedral, Improper
  • Lennard Jones and Coulomb with Cutoffs

22
More Future Work
  • Evaluation of NVT ensemble vs NPT ensemble
  • Functionality in the presence of solvent
Write a Comment
User Comments (0)
About PowerShow.com