How evolution makes proteins fold quickly (original) (raw)
Related papers
Journal of Molecular Biology, 1999
Here, we provide an analysis of molecular evolution of ®ve of the most populated protein folds: immunoglobulin fold, oligonucleotide-binding fold, Rossman fold, alpha/beta plait, and TIM barrels. In order to distinguish between``historic'', functional and structural reasons for amino acid conservations, we consider proteins that acquire the same fold and have no evident sequence homology. For each fold we identify positions that are conserved within each individual family and coincide when nonhomologous proteins are structurally superimposed. As a baseline for statistical assessment we use the conservatism expected based on the solvent accessibility. The analysis is based on a new concept of``conservatism-of-conservatism''. This approach allows us to identify the structural features that are stabilized in all proteins having a given fold, despite the fact that actual interactions that provide such stabilization may vary from protein to protein. Comparison with experimental data on thermodynamics, folding kinetics and function of the proteins reveals that such universally conserved clusters correspond to either: (i) super-sites (common location of active site in proteins having common tertiary structures but not function) or (ii) folding nuclei whose stability is an important determinant of folding rate, or both (in the case of Rossman fold). The analysis also helps to clarify the relation between folding and function that is apparent for some folds.
Evolutionary conservation in protein folding kinetics 1 1 Edited by C. R. Matthews
Journal of Molecular Biology, 2000
The sequence and structural conservation of folding transition states have been predicted on theoretical grounds. Using homologous sequence alignments of proteins previously characterized via coupled mutagenesis/kinetics studies, we tested these predictions experimentally. Only one of the six appropriately characterized proteins exhibits a statistically signi®cant correlation between residues' roles in transition state structure and their evolutionary conservation. However, a signi®cant correlation is observed between the contributions of individual sequence positions to the transition state structure across a set of homologous proteins. Thus the structure of the folding transition state ensemble appears to be more highly conserved than the speci®c interactions that stabilize it.
Evolutionary conservation in protein folding kinetics1
Journal of Molecular Biology, 2000
The sequence and structural conservation of folding transition states have been predicted on theoretical grounds. Using homologous sequence alignments of proteins previously characterized via coupled mutagenesis/kinetics studies, we tested these predictions experimentally. Only one of the six appropriately characterized proteins exhibits a statistically signi®cant correlation between residues' roles in transition state structure and their evolutionary conservation. However, a signi®cant correlation is observed between the contributions of individual sequence positions to the transition state structure across a set of homologous proteins. Thus the structure of the folding transition state ensemble appears to be more highly conserved than the speci®c interactions that stabilize it.
Protein folding as an evolutionary process
Physica A: Statistical Mechanics and its Applications, 2009
Protein folding is often depicted as a motion along descending paths on a free energy landscape that results in a concurrent decrease in the conformational entropy of the polypeptide chain. However, to provide a description that is consistent with other natural processes, protein folding is formulated from the principle of increasing entropy. It then becomes evident that protein folding is an evolutionary process among many others. During the course of folding protein structural hierarchy builds up in succession by diminishing energy density gradients in the quest for a stationary state determined by surrounding density-in-energy. Evolution toward more probable states, eventually attaining the stationary state, naturally selects steeply ascending paths on the entropy landscape that correspond to steeply descending paths on the free energy landscape. The dissipative motion of the non-Euclidian manifold is non-deterministic by its nature which clarifies why it is so difficult to predict protein folding.
Evolutionary conservation in protein folding kinetics.
The sequence and structural conservation of folding transition states have been predicted on theoretical grounds. Using homologous sequence alignments of proteins previously characterized via coupled mutagenesis/kinetics studies, we tested these predictions experimentally. Only one of the six appropriately characterized proteins exhibits a statistically signi®cant correlation between residues' roles in transition state structure and their evolutionary conservation. However, a signi®cant correlation is observed between the contributions of individual sequence positions to the transition state structure across a set of homologous proteins. Thus the structure of the folding transition state ensemble appears to be more highly conserved than the speci®c interactions that stabilize it.
Evolutionary Optimization of Protein Folding
2013
Nature has shaped the make up of proteins since their appearance, *3.8 billion years ago. However, the fundamental drivers of structural change responsible for the extraordinary diversity of proteins have yet to be elucidated. Here we explore if protein evolution affects folding speed. We estimated folding times for the present-day catalog of protein domains directly from their size-modified contact order. These values were mapped onto an evolutionary timeline of domain appearance derived from a phylogenomic analysis of protein domains in 989 fully-sequenced genomes. Our results show a clear overall increase of folding speed during evolution, with known ultra-fast downhill folders appearing rather late in the timeline. Remarkably, folding optimization depends on secondary structure. While alpha-folds showed a tendency to fold faster throughout evolution, beta-folds exhibited a trend of folding time increase during the last *1.5 billion years that began during the ''big bang'' of domain combinations. As a consequence, these domain structures are on average slow folders today. Our results suggest that fast and efficient folding of domains shaped the universe of protein structure. This finding supports the hypothesis that optimization of the kinetic and thermodynamic accessibility of the native fold reduces protein aggregation propensities that hamper cellular functions.
Evolutionary aspects of protein structure and folding
Current Opinion in Structural Biology, 2003
Four basic stages of evolution of protein structure are described, basing on recent work of the authors aimed specifically to reconstruct the earliest events in the protein evolution. According to this reconstruction, the initial stage of short peptides comprising, probably, only a few amino acid residues had been followed by formation of closed loops of 25-30 residues, which corresponds to the polymer-statistically optimal ring closure size for mixed polypeptide chains. The next stage involved fusion of relatively small linear genes and formation of protein structures consisting of several closed loops of a nearly standard size, with 4-6 loops (100-200 amino acid residues) in a typical protein fold. The last, modern stage began with combinatorial fusion of the presumably circular 300-600 bp DNA units and, accordingly, formation of multidomain proteins.
To illuminate the evolutionary pressure acting on the folding free energy landscapes of naturally occurring proteins, we have systematically characterized the folding free energy landscape of Top7, a computationally designed protein lacking an evolutionary history. Stopped-flow kinetics, circular dichroism, and NMR experiments reveal that there are at least three distinct phases in the folding of Top7, that a nonnative conformation is stable at equilibrium, and that multiple fragments of Top7 are stable in isolation. These results indicate that the folding of Top7 is significantly less cooperative than the folding of similarly sized naturally occurring proteins, suggesting that the cooperative folding and smooth free energy landscapes observed for small naturally occurring proteins are not general properties of polypeptide chains that fold to unique stable structures but are instead a product of natural selection.
To determine the extent to which protein folding rates and free energy landscapes have been shaped by natural selection, we have examined the folding kinetics of five proteins generated using computational design methods and, hence, never exposed to natural selection. Four of these proteins are complete computer-generated redesigns of naturally occurring structures and the fifth protein, called Top7, has a computer-generated fold not yet observed in nature. We find that three of the four redesigned proteins fold much faster than their naturally occurring counterparts. While natural selection thus does not appear to operate on protein folding rates, the majority of the designed proteins unfold considerably faster than their naturally occurring counterparts, suggesting possible selection for a high free energy barrier to unfolding. In contrast to almost all naturally occurring proteins of less than 100 residues but consistent with simple computational models, the folding energy landscape for Top7 appears to be quite complex, suggesting the smooth energy landscapes and highly cooperative folding transitions observed for small naturally occurring proteins may also reflect the workings of natural selection.
Evolutionary conservation of the folding nucleus
Journal of Molecular Biology, 2001
Here, we present statistical analysis of conservation pro®les in families of homologous sequences for nine proteins whose folding nucleus was determined by protein engineering methods. We show that in all but one protein (AcP) folding nucleus residues are signi®cantly more conserved than the rest of the protein. Two aspects of our study are especially important: (i) grouping of amino acid residues into classes according to their physical-chemical properties and (ii) proper normalization of amino acid probabilities that re¯ects the fact that evolutionary pressure to conserve some amino acid types may itself affect concentration of various amino acid types in protein families. Neglect of any of those two factors may make physical and biological``signals'' from conservation pro®les disappear.