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Protein Folding: Seeing is Deceiving

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Air date: Wednesday, September 15, 2010, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local
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Category: Wednesday Afternoon Lectures
Runtime: 01:19:36
Description: The protein folding problem was first recognized by Hsien Wu (1931) and Mirsky & Pauling (1936), approximately three-quarters of a century ago. The problem ‑‑ arguably the most significant unsolved problem in chemical biology ‑‑ is inherently grounded in protein thermodynamics, and thermodynamics is surely our most powerful discipline for understanding biological systems. So why does fundamental understanding of protein folding remain an unresolved question?

In work at the NIH, Anfinsen showed that a protein's three-dimensional structure is a spontaneous consequence of its amino acid sequence in water at physiological temperature and pressure. Remarkably, under dilute solution conditions, a purified protein adopts its native fold without either the addition of energy or assistance from auxiliary cellular components (chaperones notwithstanding). The fold of the protein links the one‑dimensional, linear world of DNA to the three-dimensional world of biological function; accordingly, protein folding is a cornerstone of life on earth. Yet, in essence, this self-assembly process lies within the province of biophysics, not cell biology.

The classic folding paradigm, established by Anfinsen and others, has been interpreted to mean that under folding conditions, the native fold is selected from an astronomical number of conceivable alternatives by the constellation of favorable interactions between and among its amino acid sidechains. This plausible idea is entirely consistent with the characteristic close-packing seen in protein crystal structures, where it is apparent that residues distant in sequence are juxtaposed in space, presumably providing both structural stability and topological specificity. Contrary to this view, I will discuss evidence from both experiment and simulations that the overall fold is established prior to eventual sidechain close-packing. Consequently, formation of the folded, hydrogen-bonded framework and its further stabilization via sidechain locking are separable folding events, an enormously simplifying realization.

The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.
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NLM Title: Protein folding : seeing is deceiving [electronic resource] / George Rose.
Series: NIH director's Wednesday afternoon lecture series
Author: Rose, George D.
National Institutes of Health (U.S.)
Publisher:
Other Title(s): NIH director's Wednesday afternoon lecture series
Abstract: (CIT): The protein folding problem was first recognized by Hsien Wu (1931) and Mirsky & Pauling (1936), approximately three-quarters of a century ago. The problem (arguably the most significant unsolved problem in chemical biology) is inherently grounded in protein thermodynamics, and thermodynamics is surely our most powerful discipline for understanding biological systems. So why does fundamental understanding of protein folding remain an unresolved question? In work at the NIH, Anfinsen showed that a protein's three-dimensional structure is a spontaneous consequence of its amino acid sequence in water at physiological temperature and pressure. Remarkably, under dilute solution conditions, a purified protein adopts its native fold without either the addition of energy or assistance from auxiliary cellular components (chaperones notwithstanding). The fold of the protein links the one-dimensional, linear world of DNA to the three-dimensional world of biological function; accordingly, protein folding is a cornerstone of life on earth. Yet, in essence, this self-assembly process lies within the province of biophysics, not cell biology. The classic folding paradigm, established by Anfinsen and others, has been interpreted to mean that under folding conditions, the native fold is selected from an astronomical number of conceivable alternatives by the constellation of favorable interactions between and among its amino acid sidechains. This plausible idea is entirely consistent with the characteristic close-packing seen in protein crystal structures, where it is apparent that residues distant in sequence are juxtaposed in space, presumably providing both structural stability and topological specificity. Contrary to this view, I will discuss evidence from both experiment and simulations that the overall fold is established prior to eventual sidechain close-packing. Consequently, formation of the folded, hydrogen-bonded framework and its further stabilization via sidechain locking are separable folding events, an enormously simplifying realization.
Subjects: Protein Folding
Publication Types: Lectures
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NLM Classification: QU 55.9
NLM ID: 101546241
CIT Live ID: 9518
Permanent link: http://videocast.nih.gov/launch.asp?16130

 

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