Rama Ranganathan (U. Texas Southwestern) Part 1: What is Protein Design?

www.ibiology.org/biophysics/p...
Lecture Overview:
Proteins are synthesized as linear polymers of amino acids, yet proteins spontaneously fold into complex 3 dimensional structures, fulfill biochemical functions, and are able to adapt to a changing environment. How does this “protein design” happen? In Part 1, Ranganathan explains that the transformation is directed by physical interactions between small numbers of amino acids within a protein. Most interactions are short-range but some are surprisingly long-range and interactions between amino acids in the active sites of proteins may be co-operative. Amino acids can also cluster in modules allowing different parts of a protein to have different functions.
In Part 2, Ranganathan describes a statistical approach developed by his lab to determine which amino acids in a protein drive the “design” of that protein. By studying the same protein across many species, Ranganathan and colleagues determined which amino acids were highly conserved, and thus likely important for protein function. They also tracked pairs or groups of residues where variation in one residue resulted in a change in the other residue, indicating conserved interactions. These experiments gave rise to a model in which a few, physically connected, collectively evolving groups or “sectors” of amino acids provide the “design” for natural proteins.
In his third lecture, Ranganathan describes experiments done in his lab to test the model proposed in Part 2. They find that a statistical matrix that predicts interactions between amino acids provides sufficient information to encode protein structure. Using saturation mutagenesis, Ranganathan’s lab showed that amino acids necessary for a protein function, such as ligand binding, reside within a sector. Using a similar technique, Ranganathan was able to determine which amino acids in a protein were most likely to mutate or adapt in response to selective pressure. Again, all of the amino acids identified were in a sector position. These findings support a model in which sectors provide the necessary design parameters for protein folding, function and adaptability.
Speaker Bio:
Rama Ranganathan received his B.S. in Bioengineering from the University of California, Berkeley and his Ph.D. and M.D. degrees from UC San Diego where he studied signal transduction in the invertebrate visual system. He was a post-doctoral fellow at Harvard Medical School, where he studied K+ channels, and at The Salk Institute, where he learned x-ray crystallography. He joined the Department of Pharmacology at the University of Texas, Southwestern Medical Center in 1997. Currently, Ranganathan is Professor and Director of the Green Center for Systems Biology at UT Southwestern and he is affiliated with the Departments of Biophysics and Pharmacology.
Ranganathan’s lab uses computational and experimental methods to study the structure, function and evolution of proteins at the atomic level. At the cellular level, his lab studies signal transduction in photoreceptor cells in the Drosophila eye. In both cases, the goal is to understand the evolutionary design of signaling systems.

[@MrCmusicfan]

Brilliant Brilliant lecture! A fundamental and complex problem of protein folding and function very nicely articulated. thanks!

[@Christmas12]

I'm barely able to wrap my head round this on first viewing, but i'm FASCINATED! there's something in here that's going to be very very important, it's probably going to link up with information theory way down the line after someone starts resolving the keys to this technology and there'll be at least a half dozen nobel prizes handed out to the first teams who make sense of it

[@amirshahein9090]

by the way, 'way down the line' is the next video (Part 2)

[@christeredvardsson8078]

Fantastic lecture! Very much enjoy how you introduce the topic by presenting problems and challenges, not just solutions or basic information. Love that you use relevant examples that allowed for further understanding in the field and provide references to original articles.

[@numericalcode]

Really good ideas

[@djramma86]

This is really interesting venue that one day will lead to cure of several disease and a new age in molecular medicine thank you ibiology team

[@dpatulea]

Awesome lecture! Thank you!

[@stipepavic843]

Best lecture ever, Superb!!!

[@rogerscottcathey]

Lovely lecture. Not happy with the adoption of "design" and "interrogate" into the nomenclature though.

[@patldennis]

Keep in mind that Shih Tzu's are designed. Corn is designed. Etc. Design is synonymous with in vitro/directed evolution here. It's just that the metaphor has been extended to natural selection as you point out. Let's not be afraid of the word simply bc creationists don't understand it.

[@rogerscottcathey]

6:20 ff, unknowns in surface structure have been specified in some cases as glycans