Relaxation of protein structures using FIRSTFRODA

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Relaxation of protein structures using FIRST/FRODA

• Dan Farrell
• Arizona State University

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Overview

• Steric overlap in protein X-ray crystal
  structures
• New relaxation approach FIRST/FRODA
• Results
• Future Enhancements

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Why are relaxed structures important to
FIRST/FRODA?

• FIRST
• Rigid cluster decomposition based on input
  geometry
• FRODA
• Locked-in steric overlap causes instability
• Cannot fully reach a target that has steric
  overlap

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Why are there steric overlaps in crystal
structures?

• Hydrogen placement
• Side chain and backbone freedom
• Resolution limitations

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RelaxationTraditional Method

• Molecular Dynamics--Minimize potential energy
• Bond stretching
• Bond bending
• Dihedrals
• Sterics
• Coulomb

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Some (partisan) comments on MD versus FRODA

• MD will do nanosecs. Biological functionality
  takes place millisecs.
• Thus a factor 106 to go for MD. Moores law says
  that computer power doubles every 2 years
  therefore must wait 25 years for MD to give
  answers.
• Phenomenological potentials in MD dubious,
  especially away from the native state. Not the
  gold standard
• Water makes and breaks h-bonds on nanosecs, so
  huge problem for MD. For much longer times, water
  flows to fill space, somewhat like a superfluid.
• FRODA gives large RMSDs that correspond to
  millisecs, and uses only the most important, and
  non-controversial, parts of the potential. Water
  can be ignored as it is diffusing so quickly.

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FIRST and FRODA
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FRODA Initial State
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FRODA Throw atoms
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FRODA Cycle 1 fit ghosts to atoms
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FRODA Cycle 1 move each atom along its average
mismatch vector
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FRODA Cycle 2 fit ghosts to atoms
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FRODA Cycle 2 move each atom along its average
mismatch vector
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FRODA Initial State
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FRODA no throw
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FRODA Cycle 1 fit ghosts to atoms
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FRODA Cycle 1 move each atom along its average
mismatch vector
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FRODA Cycle 2 fit ghosts to atoms
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FRODA Cycle 2 move each atom along its average
mismatch vector
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FRODA van der Waals radii

• Radii decrease
• when oppositely charged atoms interact
• donor/acceptor in potentially H-bonding geometry
• polar hydrogens reduced to 0.25 Å (except when
  interacting with another positively charged atom)
• Repulsive mismatch
• proportional to overlap
• drops to zero when overlap is small

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Relaxation with FRODA

• Dont count H-bonds and hydrophobic tethers as
  rigid constraints.
• Dont throw atoms
• Allow steric repulsion
• Allow attraction (under development)
• Keep C-alphas fixed

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Relaxing the PDB

• PDB Select List 1500 crystal structures, all
  better than 3.0 Å resolution and 30 R-factor.
• Richardson clashscore Number of atomic overlaps
  4.0 Å per 1000 atoms.

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Future Enhancements

• New stickiness routines to replace current
  attraction routines
• Ideal ghost templates

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Applications

• Large structures 106 atoms
• NMR
• CryoEM

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Acknowledgements

• Stephen Wells
• Mike Thorpe
• Brandon Hespenheide
• Scott Menor