Amino Acid Sequence Determines Protein Tertiary Structure
Several lines of evidence have been presented in favor of the notion that primary protein sequence contains all the information required for overall three-dimensional protein structure, making the idea of a de novo protein prediction possible. First, proteins with different functions usually have different amino acid sequences. Second, several different human diseases, such as Duchenne muscular dystrophy, can be linked to loss of protein function resulting from a change in just a single amino acid in the primary sequence. Third, proteins with similar functions across many different species often have similar amino acid sequences. Ubiquitin, for example, is a protein involved in regulating the degradation of other proteins; its amino acid sequence is nearly identical in species as far separated as Drosophila melanogaster and Homo sapiens. Fourth, by thought experiment, one can deduce that protein folding must not be a completely random process and that information necessary for folding must be encoded within the primary structure. For example, if we assume that each of 100 amino acid residues within a small polypeptide could take up 10 different conformations on average, giving 10^100 different conformations for the polypeptide. If one possible confirmation was tested every 10^-13 second, then it would take about 10^77 years to sample all possible conformations. However, proteins are properly folded within the body on short timescales all the time, meaning that the process cannot be random and, thus, can potentially be modeled.
One of the strongest lines of evidence for the supposition that all the relevant information needed to encode protein tertiary structure is found in the primary sequence was demonstrated in the 1950s by Christian Anfinsen. In a classic experiment, he showed that ribonuclease A could be entirely denatured by being submerged in a solution of urea (to disrupt stabilizing hydrophobic bonds) in the presence of a reducing agent (to cleave stabilizing disulfide bonds). Upon removal of the protein from this environment, the denatured and functionless ribonuclease protein spontaneously recoiled and regained function, demonstrating that protein tertiary structure is encoded in the primary amino acid sequence. Had the protein reformed randomly, over one-hundred different combinations of four disulfide bonds could have formed. However, in the majority of cases proteins will require the presence of molecular chaperons within the cell for proper folding. The overall shape of a protein may be encoded in its amino acid structure, but its folding may depend on chaperons to assist in folding.
- Primary to Tertiary
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Primary structure of human artemin (Isoform 1 )
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Tertiary structure of human artemin (PDB: 2GYR) rendered using PyMOL (Delano Scientific Freeware)
Read more about this topic: De Novo Protein Structure Prediction
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