Issues in Biology

The Protein-folding Problem and Self-assembly of Complex Structures

The folding problem addresses the relationship between the DNA sequence of a gene and the structure of a protein it encodes. How can a linearly arranged sequence encode information for a three dimensional structure? It does so in a medium that decodes the information on which amino acid residues (the building blocks of proteins) can interact closely together or not. Although the concept is extremely simple, and referred to as the hydrophobic effect, the actual dynamics of the system's behavior is stunningly complex. Protein folding and protein-protein interactions, both essential for the function of a cell, are two equivalent problem of self-assembly processes. They are both an extension of the genetic code, alas displaying an incredulous redundancy amidst a surprising reproducibility. These two properties  --  stability of structure and redundancy in sequence  --  lie at the core of any model of molecular evolution. The problem unfolds something like the following: the genes with their proper DNA sequences are the units of inheritance. The proteins, synthesized from the linear nucleic acid template, contain an amino acid sequence that corresponds to the DNA sequence according to the genetic code. This code in itself is redundant, because 64 possible codons are made combining three bases from four types of bases to choose from. These 64 codons code for only 20 different amino acids used for protein biosynthesis. In other words, there are more possible triple-base combinations available than needed to code for 20 different amino acids. Once synthesized, the linear (literally stretched out) protein strand folds into an active three dimensional structure different from this elongated initial form.

Two observations can be made. First, each protein with a particular amino acid sequence always adopts the same three dimensional, active structure. Second, proteins with different amino acids can adopt identical three dimensional structures. Taken together, single amino acid mutations (as the result of mutations in the DNA sequence of the gene) either result in the same fold, or force the protein to adopt a different structure. In both cases, the protein may retain its function, or loose it. Obviously, the position along the sequence  where the mutation occurs is important, as is the difference in chemical properties between original and mutant protein, for every mutation has the potential of affecting either structure, or function, or both. The question now remains, if a code exists (a code beyond the genetic code which describes a translation of a nucleic acid language into an amino acid language) that describes the arrangement of the amino acid within a three dimensional protein structure. The available data undoubtedly demonstrates that the redundancy of this code must be tremendous. No wonder the code is elusive. Yet, we have to understand this code in order to understand the molecular mechanism of evolution because it is the protein structures where natural selection works and 'selects' the parent (by letting it survive) carrying the DNA sequence inherited by the offspring.