college of physical and mathematical sciences
TRANSCRIPT
College of Physical and Mathematical Sciences
Protein Engineering Advances Scientific Discovery
Dr. James Moody
Chemistry and Biochemistry
801-422-6272
I use protein modeling, engineering, and crystallography to study protein function and engineer new protein-based materials.
Retrieved from: www.cellsignal.com/contents/science-cellular-landscapes/cellular-landscapes-protein-synthesis/science-landscapes-protein-
synthesis
Protein-based PRC2 disruptors
EB22Ezh2
The PRC2 core complex
The polycomb repressive complex (PRC2) methylates histones to mark sections of the genome as not needed in a given cell type or developmental stage.
EED
Suz12
Ezh2
Grafting the Ezh2 helix
Ezh2
Moody, et al. PNAS 2017 (in press)
hESC Co-IP and Western Blot
Cancer cell proliferation assay
H3K27me3Jarid2
Ezh2EED
Oct4b-tubulin
Highly specific Mdm2 and Mdm4 inhibitor proteins
Mdm2 & Mdm4 are nearly identical
Mdm4:p53Mdm2:p53
Design of an Mdm4-specfic binding protein
Mdm4:p53MB17 design model
Lyra Griffiths, Darcie Miller, Elih Velasquez, David Duda, Zhengding Su, Brenda Shulman, Richard Kriwacki, Michael Dyer, St Jude Child. Res. Hosp.
variant
variant
MB17 variant: 33 21 22 41 42 Blank
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e M
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ban
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ten
sity
Rel
ativ
e M
dm
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ban
d in
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sity
MB17 variant: 33 21 22 41 42 Blank
Cancer cell Co-IP and Western Blot
Radical SAM enzyme variant for facile crystallization
PFL-AE, SAM,and [4Fe4S] cluster from previous crystal structuresNew structure of PFL-AE-H variant
New structure of PFL-AE-H bound to 5’-dAdoElectron densityHydrogen bonds
PFL-AE-H crystals with many different ligands
Mutations do not alter protein conformation New insights into valence localization
PFL-AE[4Fe4S] clusterSAMSubstrate peptide from pyruvate formate-lyase
Archetypical radical SAM enzyme:pyruvate formate-lyase activating enzyme (PFL-AE)
Protein Therapies for Muscular Dystrophy
Pam Van Ry
Chemistry and Biochemistry
(801) 422-1540
Areas of Interest:
Protein Therapies for Muscular Dystrophy
Pulmonary Fibrosis and Interstitial Lung Disease
DystrophinGenetic
Mutation
Muscle Loss
Muscle Hypoxia
Repeated Rounds of Muscle Fiber
Membrane Damage & Repair
Oxidative Stress
Metabolic Strain
Elevated Inflammatory Response in
Muscle
Calcium Dysregulation and Enhanced Proteosome
Activity
DMD Disease Progression
Muscle Fibrosis
Altered Muscle Signaling
Necrotic Muscle Fibers
Altered Myomatrix
Utrophin EnhancementIntegrin Enhancement
Aids in Muscle Repair and Regeneration
Provides Immune Tolerance to Damaged
Muscle
Induces Neovascularization and Angiogenesis
7
Galectin-1 Protein therapy
Dysferlinopathy
Aids in Muscle Repair and Regeneration
Possible roles for Galectin-1
protein therapy
Modulates Immune response
• Stabilization of stress-induced calcium signaling and formation in transverse tubules membrane
• Oxidative Stress
Pulmonary Fibrosis and Interstitial Lung Disease
Exploring the mechanism for disease manifestation using mouse and cell based models of Pulmonary Fibrosis.
Translational endpoint measures: High resolution CT scanActivityPulmonary assessment
Ganesh Raghu, M.D.,FCCP,FACP
Professor of Medicine & Lab Medicine (Adjunct)Division of Pulmonary & Critical Care MedicineUniversity of Washington(UW)Campus Box 356175
Director, CENTER for Interstitial Lung Disease(ILD), UW Medicine,ILD, Sarcoid and Pulmonary Fibrosis ProgramCo-Director, Scleroderma Clinic, UW Medicine
What: Math Circles is an outreach program of the Math Department at Brigham Young University.
Goal: Its goal is to give students in grades K-12 a chance to learn, explore, and have fun learning about mathematics and its uses.
When: We offer free classes taught by either BYU faculty and/or students each Saturday from 9:00am-10:00am in the Talmage Building.
BYU
Circles
Cancer Research
Josh Andersen
Chemistry and Biochemistry [email protected]
(801) 422-7193
Areas of Interest:
Tumor cell growth and resistance to treatment
Adapt or die: Tumor cells must be able to survive dynamic stresses
Time
Tumormass
Chemotherapy
Metabolic stress (e.g., hypoxia)Immune factors
Chemotherapy
Protein X
Protein Y
Protein Z
= PTM
Cell survival, tumor growth,
chemoresistance
We want to identify and understand the PTMs
that control chemoresistance
signaling pathways
A fundamental challenge of modern molecular biology:Sifting out functional PTMs from an ocean of non-
functional PTMs
Hundreds of thousands of PTMs identified. However, a small percentage of these PTMs seem to have a functional impact on any given protein.
Protein Z
= PTM
Functional PTMs
Our lab has developed approaches to sift out functional PTMs that control tumor cell survival
What we need are computational approaches to complement our wet lab efforts!
Biological Mass Spectrometry& Cell Sorting Core
Daniel Mortensen
Chemistry and Biochemistry
(801) 422-7123
Areas of Interest:
Proteomics, Metabolomics, Lipidomics, and Flow Cytometry
Orbitrap Fusion Lumos(Thermo Fisher)
• The flagship instrument for proteomics experiments• More than 2000 proteins in 45 min.• Optimize / customize for your samples
[email protected] ; phone: 2-7123
[email protected] ; phone: 2-7123
6530 Accurate Mass q-ToF LCMS(Agilent)
Powerful tool for:• metabolomics• lipidomics
[email protected] ; phone: 2-7123
Mass Spectrometry Prices and Software
• Typical samples: $15 /hour• Dirty samples: $30 /hour
• PEAKS Software• Fast, high-end proteomics data processing• Quantitative analysis
• Peak Investigator• Analyzes peak shapes to increase resolution
by more than 10x
[email protected] ; phone: 2-7123
BD FACSAria Fusion flow cytometer
• Top-of-the-line cell sorter
• 4 lasers• Sort into 4 sorting tubes
or 384 well plates• $50 per use
Material Synthesis and Characterization Including Analysis of the Resulting Data
Matthew R. Linford
Chemistry and Biochemistry [email protected]
(801) 422-1524
Areas of Interest:
New materials for chromatography (TLC) and sample prep (SPME), new coatings, material characterization, and data analysis
Group Info and Sources of Funding
Linford Research Group• 8 graduate students (Cody, Tuhin, Shiladitya,
Brian, Varun, Dhananjay, Dhruv, and Tahereh)
Projects funded industrially by• Corning (display glass characterization)
• InSilixa (bioarrays)
• Moxtek (coatings)
• Restek (new materials for chromatography)
• Kurt J. Lesker (applications of atomic layer deposition)
All images from the Internet
Equipment, Deposition Tools, Data Analysis Methods
Characterization Equipment Used• X-ray photoelectron spectroscopy
• Time-of-flight secondary ion mass spectrometry
• Spectroscopic ellipsometry
• Contact angle goniometry
Deposition Methods Used• Sputtering
• Atomic layer deposition
• Chemical vapor deposition
• Wet chemical reactions
Data Analysis Tools Used• Principal component analysis
• Multivariate curve resolution
• Entropy/information content analysisAll images from the Internet
Accomplishments• Group has ca. 25 publications per year
• 300 publications total
• Editor of Applied Surface Science
• Alcuin fellow at BYU
• By Google Scholar
• Papers cited more than 7500 times
• h-Index of 36
• i10-index of 94
Research in Catalysis: Michaelis Laboratory
With Kinghorn, M. J. ACS Catal. 2017, submitted
N
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S
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N O
OHRO
RNA Polymerase inhibitor (PA-PB1 Blocker)Influenze A
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NSO
O O
Organic Crystals with NonlinearOptical Properties(THz Generation)
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O
Me
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Vitamine E DerivativesAnti-Cancer Activity
with Talley, M. R.; Stokes, R. W. Dalton Trans. 2016, 45, 9770With Walker, W. K.; Ess, D. H. J. Am. Chem. Soc. 2015, 137, 7371
With Walker, W. K. Org Lett. 2015, 17, 752
M1 M2
NN
P
tBu Ph Ph
P
tBu
PhPh
L
L L L
M2 = Pd, Pt, Ni, Rh
M1 = Ti, Al
OBnO
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with Udumula, V. ACS Catal. 2015, 5, 3457with Udumula, V.; Nazari, S. H. ACS Catal. 2016, 6, ASAPs
Snow, dust, and water quality
Greg Carling
Geological Sciences
(801) 422-2622
Areas of Interest:
Trace element and nutrient cycling, isotope geochemistry, atmospheric deposition
Desert dust and mountain snowpack
April 14, 2015
1984 2016
Google Earth
Nutrients & eutrophication
(The Salt Lake Tribune) Utah Lake State Park
(stateparks.utah.gov) Utah Lake State ParkUtah Lake Sample(Utah Division of Water Quality)
Modified from earth.usc.edu (Lund, 2000)
How machines win friends and influence people
Jacob Crandall
Computer Science [email protected]
(801) 422-7655
Areas of Interest:
- Artificial intelligence
- Human-computer cooperation
Artificial Intelligence that Cooperates with People
You own a robot
Your robot needs people skills
You send the robot into the world to do things for you
Your robot must interact with people
Play games (repeatedly) with people
New Algorithm
S#
Cooperate Defect
Cooperate 3, 3 0, 5
Defect 5, 0 1, 1
How should your robot talk?
Like Dale Carnegie:- Never complain, condemn, or criticize- Express sincere and honest appreciation- Talk in terms of the other person’s interests- Give credit to others
- Complain, condemn, and criticize- Talk in terms of yourself- Take credit
Like Spock:- No emotion; just the facts
Follow Thumper’s Rule:- If you can’t say something nice, don’t say anything at all
Like Trump:
Behaviors: S#: Fair, retaliator, forgiving EEE#: A pushover
Winning Friends
Infl
ue
nci
ng
Pe
op
le
Who do I want to talk to?
Other people studyingcooperation and relationships
Internet Measurement andAnti-Abuse
Casey Deccio
Computer Science
(801) 422-5319
Areas of Interest:
Internet measurement, including Domain Name System (DNS), DNS Security (DNSSEC), and IPv6. Internet protocol anti-abuse, including anti-spam and DDoS prevention and mitigation techniques.
DNS Reflection Attack
Attackers
IP Network
DNS Server
How can a server reliably
detect and dropspoofed requests?
Declarative Network
Capabilities
Declarative Capabilities
Existing solutions can’t be both enforceable and backward compatible
Spoofedrequestsreflected
1
2
Attackers
IP Network
CapabilitiesAware
DNS Server
1
Capabilities
2
3 Spoofedrequestsdropped
4
Proposed solution is both enforceable and backward
compatible
DNS-Based Attack and Defense
APPLIED MATHEMATICS
Jared Whitehead
Mathematics
(801) 422-2131
Areas of Interest: Fluid Dynamics (Computation, experiment, and analysis)
Uncertainty Quantification (Bayesian statistics and stochastic effects)
Data Assimilation (Bayesian and variational approaches)
Geophysics (Geologic processes, weather, and climate)
Stability of dynamical processes (linear and nonlinear/energetic)
Asymptotics (formal and rigorous verification)
Variational Methods (Lagrangian Mechanics)
Recently/currently worked/published
in the following areas:
1)Climate modeling.
2)Turbulent convection.
3)Convection in the Earth’s mantle.
4)Improved pressure estimation in
experimental fluid dynamics.
5)Parameter estimation and
uncertainty quantification for
seismic events in Indonesia.
6)Nonlinear stability under a
stochastic forcing.
7)Data assimilation for weather,
climate, and experimental fluid
dynamics.
8)Convince me it is interesting… [email protected]
If you have Math ‘problems’ that could use a
Mathematician’s expertise, we are happy to help. We have a
seminar where you can share these things…
In addition to faculty, we have several qualitatively skilled
and trained students.
If you are interested, please contact me: