Title: NMR Steered Sampling Conformation Sampling via MC Rotation of Dihedrals Selected from NMR Experiment
1NMR Steered SamplingConformation Sampling via
MC Rotation of Dihedrals Selected from NMR
Experiments
Jan 19th 2004
2Motivation
- Robust conformation sets needed
- for effective docking
- How to sample
- 3N phase space?
- Energy barriers
- Experimental data
- to guide sampling
3Sampling
- Definition
- Our Contribution
4Methods and Metrics
- Propagator
- Rotation Algorithm
- Conformation String Generation
- Cluster Analysis
Ubiquitin
BPTI
Butane
5Propagator
6Rotation
- 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
8Evaluation - BPTI
9Evaluation - BPTI
10Evaluation - BPTI
11Evaluation - Ubiquitin
12Evaluation - Ubiquitin
13Evaluation - Ubiquitin
14NMR 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
16Acknowledgements
- 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 18Evaluation - Butane
HMC
CDHMC
MD
MD
19Conformation 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
20Cluster 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
21Simulation 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
22More Future Work
- Evaluation of NVT ensemble vs NPT ensemble
- Functionality in the presence of solvent