Computational and experimental investigations of forces in protein folding

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Title: Computational and experimental investigations of forces in protein folding
Author: Schell, David Andrew
Abstract: Properly folded proteins are necessary for all living organisms . Incorrectly folded proteins can lead to a variety of diseases such as Alzheimer ?s Disease or Bovine Spongiform Encephalitis (Mad Cow Disease ) . Understanding the forces involved in protein folding is essential to the understanding and treatment of protein misfolding diseases . When proteins fold , a significant amount of surface area is buried in the protein interior . It has long been known that burial of hydrophobic surface area was important to the stability of the folded structure . However , the impact of burying polar surface area is not well understood . Theoretical results suggest that burying polar groups decreases the stability , but experimental evidence supports the belief that polar group burial increases the stability . Studies of tyrosine to phenylalanine mutations have shown the removal of the tyrosine OH group generally decreases stability . Through computational investigations into the effect of buried tyrosine on protein stability , favorable van der Waals interactions are shown to correlate with the change in stability caused by replacing the tyrosine with phenylalanine to remove the polar OH group . Two large -scale studies on nearly 1000 high -resolution x -ray structures are presented . The first investigates the electrostatic and van der Waals interactions , analyzing the energetics of burying various atom groups in the protein interior . The second large -scale study analyzes the packing differences in the interior of the protein and shows that hydrogen bonding increases packing , decreasing the volume of a hydrogen bonded backbone by about 1 .5 ?3 per hydrogen bond . Finally , a structural comparison between RNase Sa and a variant in which five lysines replaced five acidic groups to reverse the net charge is presented . It is shown that these mutations have a marginal impact on the structure , with only small changes in some loop regions .
URI: http : / /hdl .handle .net /1969 .1 /1526
Date: 2005-02-17


Computational and experimental investigations of forces in protein folding. Available electronically from http : / /hdl .handle .net /1969 .1 /1526 .

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