Biochemistry 300 Introduction to Structural Biology Walter Chazin 5140 BIOSCI/MRBIII

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Presentation transcript:

Biochemistry 300 Introduction to Structural Biology Walter Chazin 5140 BIOSCI/MRBIII Jan. 10, 2007

MESDAMESETMESSRSMYN AMEISWALTERYALLKINCAL LMEWALLYIPREFERDREVIL MYSELFIMACENTERDIRATV ANDYINTENNESSEEILIKENM RANDDYNAMICSRPADNAPRI MASERADCALCYCLINNDRKI NASEMRPCALTRACTINKAR KICIPCDPKIQDENVSDETAVS WILLWINITALL 3D structure What is Structural Biology? Organism Cell System Dynamics Cell Structures SSBs polymerase Assemblies helicase primase Complexes Sequence Structural Scales

 Determine atomic structure to analyze why molecules interact Atomic Resolution Structural Biology

Anti-tumor activity Duocarmycin SA The Reward: Understanding  Control Shape Atomic interactions

Atomic Structure in Context Molecule Structural Genomics Pathway Structural Proteomics Activity Struct. Systems Biol. RPA NER BER RR

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

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!)

Complementarity of the Atomic 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

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 Which is the biologically relevant conformer? Does the molecule crystallize in the biologically relevant conformation?

Representation of Structure Conformational Ensemble Variability reflected in the RMSD of the ensemble Neither crystal nor solution structures can be properly represented by a single conformation  Intrinsic motions  Imperfect data

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