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BiomolecularInteractions and...
Transcript of BiomolecularInteractions and...
Biomolecular Interactions and Pathways (L)
Administrative noteFinal is comprehensive, based on lecture notes on Web
If while studying the notes you have a question –Send me an email. I will reply promptly to all.
Next Monday, here as usual
Pathways (L1)
� We’ve talked a lot about individual proteins
� But proteins tend to interact
� Here is the relevant heirarchy (see next)
Pathways and Networks
� Pathway:
� a sequence of interacting biomolecules
� Network:
� interacting pathways
� But the dividing line is not sharp
Graphs for Paths & Networks
� Biomolecules are nodes (vertices, vertexes)
� Interactions are arcs (edges, links, lines)
� Arcs may be labeled with e.g. an enzyme
Example Pathway & Network
Figure 3. A possible regulatory pathway of growth, differentiation and apoptosis in neuroblastoma or neuronal cells. (Source: A. Nakagawara, Trk receptor tyrosine kinases: A bridge between cancer and neural development, Cancer Letters, http://www1.elsevier.com/homepage/sab/oncoserve/cl_mr/nakag.htm.)
Example Pathway & Network II
Figure 2. Model of apoptotic pathway of sympathetic neurons induced by NGF withdrawal or p75NTR activation. DeltaNp73 is a splicing variant of the p73 candidate tumor suppressor. (Source: A. Nakagawara, Trk receptor tyrosine kinases: A bridge between cancer and neural development, Cancer Letters, http://www1.elsevier.com/homepage/sab/oncoserve/cl_mr/nakag.htm.)
How can pathways/networks be determined?
� You can do “wet lab” experiments
� You can study mutants
� Mutate different genes � same mutant phenotype
� What does that suggest?
How can pathways/networks be determined?
� Mutate different genes � same mutant phenotype
� What does that suggest?
� The genes are on the same pathway
� Can you use this method to find protein pathways?
� You can study data from
� Microarrays, 2D-PAGE, MS, etc.
� What is 2D-PAGE? Could you use related methods?
� Biomolecules with similar profiles across conditions…
� …are likely on the same pathway
How can pathways/networks be determined?
� Wet lab experiments, mutants, expression data…
� Which of these have we mentioned?
� Analysis of the literaturome� (usually, euphoniously but foolishly called “bibliome”)
(New Topic)
From “it interacts” to reaction rates and levels
� Modeling and simulation of chemical processes is mathematically complex
� One approach is differential equations
� What does the LHS mean?
� The RHS might be some function of the substrate concentration (p191)� How would concentration & temperature affect the LHS?
blahblahdt
dP =
From “it interacts” to reaction rates and levels
� Modeling and simulation of chemical processes is mathematically complex
� One approach is differential equations
� P for the amount of product chemical
� The RHS might be some function of the substrate concentration (p191)� How would concentration & temperature affect the LHS?
blahblahdt
dP =
The Interactome (L2)
� Yet another –ome to discuss! (p197)
� Interactome:
� set of all protein interactions in a cell
� what would an interactome look like?
� (That is, if we were to put it on paper)
Matching the Fingerprint -Cautions
� Different orders of the same AAs can lead to a mistaken assessment of match� Fortunately, this rarely happens
� Leucine and isoleucine have the same mass� Fortunately, for DB lookup it “does not have a practical impact” – Westhead et al. p. 187
� Subsequences of Ks and Rs are cleaved randomly (RKK, RK, etc.)� Makes the algorithms a little more complicated, no big deal
� Etc.…see pp. 187-188.
Displaying the Interactome
� The interaction network graph approach
� Shown are just 1500 proteins of about 6000
� Humans have about 30000
� It works, sort of, but is a bit overwhelming!
� Solution:
� cluster “functionally similar” proteins (p197)
� Result is a functional interaction map (see next)
Half of a functional interaction map
Source: Tucker et al., Toward an understanding of complex protein networks, Trends Cell Biol 11: 103, 201.
Functional Interaction Map Redux
It shows which functional protein types tend to interact
Models for Higher Order Entities
Recall:
What we’ve talked about
earlier today
The subject of section L3
Take a different course…
Models for Higher Order Entities III
� A cell in a complex organism is animorphic
� Just kidding, but it is polymorphic
� It is a kidney cell, or a 12” spine cell, etc.
� Different organisms in a sense…
� ….using different genes and proteins to do its thing
� Do kidney and spinal cells have different interactomes??
Cell Modeling
� We wish to model processes, organelles, 3-D structure…and more
� The Virtual Cell (www.nrcam.uchc.edu) is an online model that can simulate a cell
Tissue and Organ Modeling
� Tissues are made of cells
� Organs are made of tissues
� Modeling and simulating an organ is a different ball game
� We’re in the domain of physiology here
� (Not so much standard bioinformatics)
Organisms� Organisms involve many processes
� Homeostasis must be maintained
� Major non-homeostatic processes exist� Development� Reproduction� Social behavior (for some organisms)� Reaction to environmental stimuli
� Bioinformatics gets involved e.g. in designing drugs that interfere with disease processes� Drug molecules must affect pathways
� which affect networks which affect the interactome� which affects tissues which affect organs � which finally affect organisms!
Populations
� Organisms group into populations
� What questions can be asked about populations
� but not individual organisms?
Ecosystems
� Sets of populations form ecosystems
� What questions can be asked about ecosystems
� but not individual populations?
Biosphere
� Sets of all ecosystems forms the biosphere
� What questions can be asked about the biosphere
� but not individual ecosystems?