Relaxation of protein structures using FIRSTFRODA

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Relaxation of protein structures using FIRSTFRODA

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Steric overlap in protein X-ray crystal structures. New relaxation approach: FIRST/FRODA ... Why are there steric overlaps in crystal structures? Hydrogen placement ... – PowerPoint PPT presentation

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Title: 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