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![Page 1: -A cell is an organization of millions of molecules -Proper communication between these molecules is essential to the normal functioning of the cell -To.](https://reader035.fdocuments.in/reader035/viewer/2022062407/56649eaa5503460f94baeb30/html5/thumbnails/1.jpg)
-A cell is an organization of millions of molecules
-Proper communication between these molecules is essential to the normal functioning of the cell
-To understand communication between molecules
*determine the arrangement of the atoms*
*Atomic Resolution Structural Biology**Atomic Resolution Structural Biology*
Organ Organ Tissue Tissue Cell Cell Molecule Molecule Atoms Atoms
Medicine and Biology at the Atomic ScaleMedicine and Biology at the Atomic Scale
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High Resolution Structural BiologyHigh Resolution Structural BiologyUsing atomic structure to understand how Using atomic structure to understand how
biomolecules communicatebiomolecules communicate
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Anticancer DrugDuocarmycin SA
Biological Specificity from StructureBiological Specificity from Structure
Shape
Atomic interactions
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Putting Structures in ContextPutting Structures in Context
MoleculeStructural Genomics
PathwayStructural Proteomics
ActivitySystems Biology
RPARPA
NER
BER
RR
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Strategy and ApproachesStrategy and Approaches
NMR Spectroscopy X-ray Crystallography
Computation
It’s not about the structure or the technique,it’s about the Biology!!!!
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Determination of 3D StructuresDetermination of 3D Structures
X-ray NMR
X-rayDiffraction
Pattern RF
RFResonance
H0
Direct detection ofatom positions
Crystals
Indirect detection ofH-H distances
In solution
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Static Structure/Dynamic BiologyStatic Structure/Dynamic Biology
• 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: visualization
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Challenges for Converting Challenges for Converting Structure to FunctionStructure to Function
• Neither crystal nor solution structures are properly represented by a single low energy conformer
• To be called a structure (not a model), there must be a complete representation of what parts are well known and what parts are not well known
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Conformational EnsembleConformational Ensemble: : Representing Representing aa Structure Structure
C
N
Uncertainty/Precision: RMSD of the ensemble
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Unique ContributionsUnique Contributions
• X-ray crystallography- highest resolution structures; fast
• NMR- enables widely varying solution conditions; characterization of motions and dynamic, weakly interacting systems
• Computation- fundamental understanding of structure, dynamics and interactions; models without experiment
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Center for Structural BiologyCenter for Structural Biology
• Increase molecular thinking
• Foster multi-disciplinary research
• Focal point bridging medicine and biology to math, physics, chemistry
• >12 research groups (8 new!!)
• Promote collaborations involving structural Promote collaborations involving structural biology researchbiology research
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How Does NMR Work?How Does NMR Work?
Ho
parallel
anti-parallel
Alignment Energy
E = h Ho
Efficiency factor-nucleus
Constants Strength ofmagnet
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Resonance: Perturb EquilibriumResonance: Perturb Equilibrium
ap
hE
p
ap
p
equilibrium
non-equilibrium
If energy is input at exactly the right frequency (), it gets absorbed
E
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Resonance: Read Out SignalsResonance: Read Out Signals
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Ho =
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1. force non-alignment 2. release
p
ap
p
ap
p
ap
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NMR of MoleculesNMR of Molecules
CH3-CH2-OH
Resonance assignment: which signal for which H atoms?
OH CH2 CH310 0
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Challenges of NMR on ProteinsChallenges of NMR on Proteins
• Proteins have hundreds/thousands of signals
• Resonance assignment is a huge challenge
• Need to use computer programs to convert from NMR data to structures
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Uses of Solution NMR to Uses of Solution NMR to Elucidate Protein FunctionElucidate Protein Function
• Analytical and Physical Characterization
– Is the protein folded?
– Sequence, post-translational modifications
– Important: measure binding constants
• Assess structural homology/effect of mutations
• Three-dimensional structure determination
• UniqueUnique: Measure flexibility/dynamics: Measure flexibility/dynamics
*To address “static structure/dynamic biology”**To address “static structure/dynamic biology”*