Protein Folding, Structure Balance And Evolution

Proteins are macromolecules that constitute the body of living-beings. Protein molecules have regular structures which are thermodynamically stable natural conformations. The native structure of protein results from a balance of many interactions. Protein folding is the process that a protein transforms from the denatured state to its specific biologically active conformation. Unraveling the mechanism of protein folding is a core subject of modern molecular biology. Until Aug, 2006, there have been more than 35000 structures in RCSB Protein Data Bank. The availability of so many structures provides good chance for the study of protein folding and structure balance.The filed of protein folding research has two branches: folding in vivo and folding in vitro. The former concentrates on the roles played by molecular chaperones in the protein folding process, while the the latter mainly pay attention to the underlying physical and chemical mechanisms of protein folding. Nowadays, most of our knowledge about the mechanism of protein folding comes from the results of experiment in vitro and the corresponding theoretical analysis. According to experimental observations, the dynamic behaviors of protein folding can be roughly classified into two classes: two-state folding and multi-state folding. These two folding scenarios have been verified by computer simulation. The synergy of experiment and simulation boost the progress of our knowledge about the mechanism of protein folding.A key step to the end of revealing the mechanism of protein folding is to find the factors that correlated with the folding rates. In the past few years, it has been found that the structural facotors have significant correlations with the protein folding rates, which initiates the research of folding mechanism from the perspective of structures.In the present work, we adopted a different point of view to explore the folding mechanism from the viewpoint of amino acid composition, and proposed a composition-based folding rate predictor: Composition Index (CI). Based on the high (R > 0.7) correlation between CI and the folding rates, we discussed the significance of amino acid composition, especially the structure of residue side chain, in the mechanism of protein folding.Although the two kinds of protein folding behaviors have been observed for many years, what determines the folding type of a protein is still largely unclear. In the present work, we investigated the determining factors of protein folding type by comparing the structural features of the two classes of proteins and found that the amino acid composition and the long-range-interaction-based topological complexity of tertiary structure are the main determinants of protein's folding type. Based on this finding, we have tried to predict the folding type of a protein from its amino acid composition, and accuracy more than 80% is achieved.The present work also studied the mass balance and charge balance in the protein 3D structures. Through analyzing crystal structures with high X-ray resolution, we found that the mass is well balanced in the protein 3D structures. The mass balance in protein 3D structure is necessary for proteins to properly function in the gravity filed of the earth. In addition, as a contrast, we also studied the charge balance in the protein tertiary structures, and found that the charge balance is not as good as the mass balance. The proteins belonging to the GO cell component functional group have larger electric polarity, which may be a reflection of the importance of electrostatic force in the building of the cellular frameworks.In addition, some aspects of protein evolution were also studied in the present work. By examing the relationship between the CvP-bias (difference between proportions of charged and polar non-charged amino acids) of seven barophilic microbes'proteomes and their optimal growth temperature, we found a statistically significant linear correlation, indicating the validity of CvP-bias for discriminating the growth temperature of oceanic barophilic microbes, which is helpful to building a self-consistent model for the last common ancestor. On the link between atmospheric oxygen rise and organism complexity increase, Acquisti et al. recently investigated the oxygen content variation in the domains of membrane proteins and proposed a hypothesis that oxygen-rich amino acids may be reduced in a reducing atomsphore and thus selected against during evolution. In the present work, we argued with them and proposed an alternative explanation on the oxygen content variation of the outer domain of membrane protein, i.e., the the unique properties of oxygen-rich amino acids and their key roles played in establishing cellular communication rather than the variation of the oxygen concentration in atomsphore are the reasons why the oxygen contents increase in the outside domain of membrane protein during evolution.