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?