Lecture 11 - September 18, 2006, Lecture 11 Announcements:...

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September 18, 2006, Lecture 11 Announcements: Assignments for the week: As in LG for 9/20 & 9/22; Do RasMol Hemoglobin, NOT Protein Data Bank Friday's lecture: That the native protein structure has the lowest free energy is not obvious. It is an experimental fact, proven by denaturation/renaturation experiments. Starting from a randomly folded polypeptide, without any other "factors" or "folding enzymes", the Mb native structure appears. For ribonuclease, disulfide bonds must be broken in order to completely unfold this protein, then the disulfides must be re-formed, but still the protein refolds spontaneously into its native structure. In these cases, researchers demonstrated that there was no requirement for “folding machinery” to find the native structure. That proteins can fold in such a short time, typically minutes, is also not well understood. Proteins have internal motion (i.e. not just the entire protein rotating and moving in solution). For HIV protease, part of the protein moves when it binds its peptide substrate. For hexokinase, glucose binding causes a large change in this protein's structure, forming the binding pocket for the other substrate, ATP. In the case of Mb, much smaller movements of the protein occur, thereby providing paths that allow oxygen to get into the protein interior to bind to the heme, and allowing the oxygen also to leave the Mb. How does a protein fold? (1) Perhaps bits of secondary structure form in solution, sometimes the "right" II structures that appear in the final folded protein, sometimes the "wrong" II structures that are not in the final folded protein. But at some point, within seconds or minutes after synthesis on the ribosome, the II structures all come together because of the hydrophobic effect into a structure that is close to the final fold, called a "molten globule". This so-called molten globule is not fully packed, and has extra space and extra motion. Within seconds or perhaps minutes, the final structural domain forms. Or, (2) the very first important event is the hydrophobic effect, which "collapses" the unfolded protein directly into the "molten globule", and only then to all the proper II structures appear. Today’s Lecture Back to the issue of protein folding: Can we calculate the final folded structure, given the AA sequence? Work to correlate the tendency of each AA to be in a particular type of secondary structure has advanced well, and prediction of secondary structure from AA sequence is very good. In contrast, predicting how the bits of II structure pack with
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This note was uploaded on 02/13/2008 for the course BIOBM 3310 taught by Professor Feigenson,gw during the Fall '07 term at Cornell University (Engineering School).

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Lecture 11 - September 18, 2006, Lecture 11 Announcements:...

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