RNaseA Nobel Prizes: Difference between revisions

== '''Introduction''' ==

Ribonuclease A has been the subject of [[Nobel Prizes for 3D Molecular Structure|Nobel Prizes on Protein Folding]] and Solid Phase Peptide Synthesis.<ref name="Raines"> PMID:11848924</ref> The observation of ribonuclease folding helped Christian Anfinsen win the Nobel Prize in 1972 for his work on protein folding <ref>'Anfinsen Nobel Lecture' [http://nobelprize.org/nobel_prizes/chemistry/laureates/1972/anfinsen-lecture.html]</ref>. The presence of four disulfide bonds and two ''cis'' proline residues in the structure of RNase A greatly affects the structure and folding kinetics of RNase A <ref>'Anfinsen Nobel Biography' [http://nobelprize.org/nobel_prizes/chemistry/laureates/1972/anfinsen-bio.html]</ref>. When RNase A undergoes reductive denaturation, it spontaneously folds back on itself to form the same structure.  The development of solid phase synthesis by Bruce Merrifield (Nobel Prize 1984) was a radical departure from traditional methods of bio-molecular synthesis that greatly increased efficiency. His method made possible the syntheses of much larger and more complex molecules; however, solid phase synthesis was not fully embraced until he demonstrated its full ability with the complete synthesis of Ribonuclease A.[http://nobelprize.org/nobel_prizes/chemistry/laureates/1984/merrifield-lecture.pdf]

The <scene name='Sandbox_Reserved_197/Cis-proline114/3' target='0'>Asn113-Pro114</scene> peptide bond also resides in a ''cis'' conformation in its folded structure, but exists in the ''trans'' conformation in its unfolded state; therefore, steric restraints imposed by the rest of the protein must be responsible for this ''cis'' conformation. Unlike P93A, the insertion of a <scene name='Sandbox_Reserved_197/P114g/3' target='0'>P114G</scene> point mutation causes the peptide bond to adopt a ''trans'' conformation and causes a 9.3 Å movement of the loop <ref>PMID:16199662</ref>. The kinetic rate and overall native conformation are not significantly effected by this mutation; however, locally, a rearrangement of the hydrogen-bonding network occurs. Results of this mutation confirm that steric hinderance of the protein can lead to formation of the ''cis'' conformation by a proline and is further energetically stabilized by hydrogen bonding, Van der Waals, and electrostatic interactions within the protein.  

Another important role of proline residues is their involvement in β turns. β turns are 180° turns commonly found in globular proteins to allow for a compact structure by connecting the ends of adjacent antiparallel β sheets [http://en.wikipedia.org/wiki/Beta_sheet]. The turn consists of a sequence of four amino acid residues. The carbonyl of the first amino acid hydrogen bonds with the amino group of the fourth amino acid. Proline is involved in β turns because it is small, flexible, and assumes a ''cis'' conformation, all attributes that allow for formation of a turn. In RNase A both Pro93 and Pro114 are involved in β turns.<ref name="Raines" /> Proline residues are important to protein folding because their ability to form a favorable ''cis'' conformation allows for thermodynamic favorability of β turn formation. With β turns, amino acids can fold back on themselves allowing the protein to reside in a compact, globular structure.