Biochemistry 300 Introduction to Structural Biology

1
Biochemistry 300Introduction to Structural
Biology
Jan. 10, 2007

• Walter Chazin
• 5140 BIOSCI/MRBIII
• E-mail Walter.Chazin_at_vanderbilt.edu
• http//structbio.vanderbilt.edu/chazin/classnotes/
  

2
What is Structural Biology?
Sequence
Structural Scales
MESDAMESETMESSRSMYNAMEISWALTERYALLKINCALLMEWALLYIP
REFERDREVILMYSELFIMACENTERDIRATVANDYINTENNESSEEILI
KENMRANDDYNAMICSRPADNAPRIMASERADCALCYCLINNDRKINASE
MRPCALTRACTINKARKICIPCDPKIQDENVSDETAVSWILLWINITALL
polymerase
SSBs
Complexes
helicase
primase
Assemblies
Cell Structures
System Dynamics
3
Atomic Resolution Structural Biology

• Determine atomic structure to analyze why
  molecules interact

4
The Reward Understanding?Control
Shape
5
Atomic Structure in Context
6
Current Strategy for Atomic Resolution Structural
Biology

• Break down complexity so that the system can be
  understood at a fundamental level
• Build up a picture of the whole from the
  reconstruction of the high resolution pieces

7
Approaches to Atomic Resolution Structural Biology

• NMR Spectroscopy X-ray
  Crystallography
• Computation

• Determine experimentally or model 3D structures
  of biomolecules
• ESR/Fluorescence to measure distances when
  traditional methods fail
• EM/Scattering to get snapshots of whole
  molecular structures
• (Cryo-EM starts to approach atomic resolution!)

8
Complementarity of theAtomic Resolution Methods

• X-ray crystallography- highest resolution
  structures faster than NMR
• NMR- enables widely varying solution conditions
  characterization of motions and dynamic, weakly
  interacting systems
• Computation- fundamental understanding of
  structure, dynamics and interactions (provides
  the why answers) models without experiment very
  fast

9
Is There A Structure?

• To correctly represent 3D structure (not a
  model), the uncertainty in each atomic coordinate
  must be represented
• Polypeptides are dynamic and therefore occupy
  more than one conformation- structural dynamics

10
Representation of Structure Conformational
Ensemble

• Neither crystal nor solution structures can be
  properly represented by a single conformation
• Intrinsic motions
• Imperfect data

Variability reflected in the RMSD of the ensemble
11
Challenges For Understanding The Meaning of
Structure

• Structures determined by NMR, computation, and
  X-ray crystallography are static snapshots of
  highly dynamic molecular systems

• Biological process (recognition, interaction,
  chemistry) require molecular motions (from
  femto-seconds to minutes)
• New methods are needed to comprehend and
  facilitate thinking about the dynamic structure
  of molecules- structural dynamics