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PubMed1974

Amino acid difference formula to help explain protein evolution.

A formula for diference between amino acids combines properties that correlate best with protein residue substitution frequencies: composition, polarity, and molecular volume. Substitution frequencies agree much better with overall chemical difference between exchanging residues than with minimum base changes between their codons. Correlation coefficients show that fixation of mutations between dissimilar amino acids is generally rare.

Amino Acids↗
PubMedDate not supplied

Heterotachy and functional shift in protein evolution.

Study of structure/function relationships constitutes an important field of research, especially for modification of protein function and drug design. However, the fact that rational design (i.e. the modification of amino acid sequences by means of directed mutagenesis, based on knowledge of the three-dimensional structure) appears to be much less efficient than irrational design (i.e. random mutagenesis followed by in vitro selection) clearly indicates that we understand little about the relationships between primary sequence, three-dimensional structure and function. The use of evolutionary approaches and concepts will bring insights to this difficult question. The increasing availability of multigene family sequences that has resulted from genome projects has inspired the creation of novel in silico evolutionary methods to predict details of protein function in duplicated (paralogous) proteins. The underlying principle of all such approaches is to compare the evolutionary properties of homologous sequence positions in paralogs. It has been proposed that the positions that show switches in substitution rate over time--i.e., 'heterotachous sites'--are good indicators of functional divergence. However, it appears that heterotachy is a much more general process, since most variable sites of homologous proteins with no evidence of functional shift are heterotachous. Similarly, it appears that switches in substitution rate are as frequent when paralogous sequences are compared as when orthologous sequences are compared. Heterotachy, instead of being indicative of functional shift, may more generally reflect a less specific process related to the many intra- and inter-molecular interactions compatible with a range of more or less equally viable protein conformations. These interactions will lead to different constraints on the nature of the primary sequences, consistently with theories suggesting the non-independence of substitutions in proteins. However, a specific type of amino acid variation might constitute a good indicator of functional divergence: substitutions occurring at positions that are generally slowly evolving. Such substitutions at constrained sites are indeed much more frequent soon after gene duplication. The identification and analysis of these sites by complementing structural information with evolutionary data may represent a promising direction to future studies dealing with the functional characterization of an ever increasing number of multi-gene families identified by complete genome analysis.

Amino Acid Substitution↗
PubMed2002

An Efficient Ligation Method in the Making of an in vitro Virus for in vitro Protein Evolution.

The "in vitro virus" is a molecular construct to perform evolutionary protein engineering. The "virion (=viral particle)" (mRNA-peptide fusion), is made by bonding a nascent protein with its coding mRNA via puromycin in a test tube for in vitro translation. In this work, the puromycin-linker was attached to mRNA using the Y-ligation, which was a method of two single-strands ligation at the end of a double-stranded stem to make a stem-loop structure. This reaction gave a yield of about 95%. We compared the Y-ligation with two other ligation reactions and showed that the Y-ligation gave the best productivity. An efficient amplification of the in vitro virus with this "viral genome" was demonstrated.

Journal Article↗
PubMed1987

Accumulation pattern of amino acid substitutions in protein evolution.

A simple method for the evolutionary analysis of amino acid sequence data is presented and used to examine whether the number of variable sites (NVS) of a protein is constant during its evolution. The NVSs for hemoglobin and for mitochondrial cytochrome c are each found to be almost constant, and the ratio between the NVSs is close to the ratio between the unit evolutionary periods. This indicates that the substitution rate per variable site is almost uniform for these proteins, as the neutral theory claims. An advantage of the present analysis is that it can be done without knowledge of paleontological divergence times and can be extended to bacterial proteins such as bacterial c-type cytochromes. It is suggested that the NVS of cytochrome c has been almost constant even over the long period (ca. 3.0 billion years) of bacterial evolution but that at least two different substitution rates are necessary to describe the accumulated changes in the sequence. This "two clock" interpretation is consistent with fossil evidence for the appearance times of photosynthetic bacteria and eukaryotes.

Amino Acid Sequence↗
PubMed2003

Testing homology with Contact Accepted mutatiOn (CAO): a contact-based Markov model of protein evolution.

Point Accepted Mutation (PAM) is the Markov model of amino acid replacements in proteins introduced by Dayhoff and her co-workers (Dayhoff et al., 1978). The PAM matrices and other matrices based on the PAM model have been widely accepted as the standard scoring system of protein sequence similarity in protein sequence alignment tools. Here, we present Contact Accepted mutatiOn (CAO), a Markov model of protein residue contact mutations. The CAO model simulates the interchanging of structurally defined side-chain contacts, and introduces additional structural information into protein sequence alignments. Therefore, similarities between structurally conserved sequences can be detected even without apparent sequence similarity. CAO has been benchmarked on the HOMSTRAD database and a subset of the CATH database, by comparing sequence alignments with reference alignments derived from structural superposition. CAO yields scores that reflect coherently the structural quality of sequence alignments, which has implications particularly for homology modelling and threading techniques.

Amino Acid Sequence↗
PubMed1994

Volume changes in protein evolution.

We have determined the variations in volume that occur during evolution in the buried core of three different families of proteins. The variation of the whole core is very small (approximately 2.5%) compared to the variation at individual sites (approximately 13%). However, by comparing our results to those expected from random sequences with no correlations between sites, we show that the small variation observed may simply be a manifestation of the statistical "law of large numbers" and not reflect any compensating changes in, or global constraints upon, protein sequences. We have also analysed in detail the volume variations at individual sites, both in the core and on the surface, and compared these variations with those expected from random sequences. Individual sites on the surface have nearly the same variation as random sequences (24% versus 28% variation). However, individual sites in the core have about half the variation of random sequences (13% versus 30%). Roughly, half of these core sites strongly conserve their volume (0 to 10% variation); one quarter have moderate variation (10 to 20%); and the remaining quarter vary randomly (20 to 40%). Our results have clear implications for the relationship between protein sequence and structure. For our analysis, we have developed a new and simple method for weighting protein sequences to correct for unequal representation, which we describe in an Appendix.

Algorithms↗
PubMed1990

Phosphoprotein and nucleocapsid protein evolution of vesicular stomatitis virus New Jersey.

The entire phosphoprotein (P) and nucleocapsid (N) protein gene sequences and deduced amino acid sequences for 18 selected vesicular stomatitis virus isolates representative of the natural genetic diversity within the New Jersey serotype are reported. Phylogenetic analysis of the data using maximum parsimony allowed construction of evolutionary trees for the individual genes and the combined N, P, and glycoprotein (G) genes of these viruses. Virtually identical rates of nucleotide substitutions were found for each gene, indicating that evolution of these genes occurs at essentially the same rate. Although up to 19 and 17% sequence differences were evident in the P and N genes, respectively, no variation in gene length or evidence of recombinational rearrangements was found. However, striking evolutionary differences were observed among the amino acid sequences of vesicular stomatitis virus New Jersey N, P, and G proteins. The N protein amino acid sequence was the most highly conserved among the different isolates, indicating strong functional and structural constraints. Conversely, the P protein amino acid sequences were highly variable, indicating considerably fewer constraints or greater evolutionary pressure on the P protein. Much of the remarkable amino acid variability of the P protein resided in a hypervariable domain located between amino acids 153 and 205. The variability within this region would be consistent with it playing a structural role as a spacer to maintain correct conformational presentation of the separate active domains of this multifunctional protein. In marked contrast, the adjacent domain I of the P protein (previously thought to be under little evolutionary constraint) contained a highly conserved region. The colocalization of a short, potentially functional overlapping open reading frame to this region may explain this apparent anomaly.

Amino Acid Sequence↗
PubMed2002

Perspectives on protein evolution from simple exact models.

Understanding the evolution of biopolymers is important to rationalise the directed and undirected design of functional molecules. Large scale experiments or detailed computational studies are often impractical. Therefore, simple model systems, such as RNA secondary structure and lattice proteins have been adapted to study general statistical and topological features of genotype (sequence) to phenotype (structure) maps. We review findings from such models that address aspects of thermodynamic and mutational robustness, neutral evolution and recombination of proteins. We compare various modelling approaches, and discuss their generality, parameter dependency and experimental verifications of their predictions. The most striking observation is the universal emergence of neutral nets--sets of phenotypically identical genotypes that are interconnected by series of point mutations. However, fast adaptation by point mutations appears to be problematic for proteins. This may explain why proteins appear to be more specific while RNA is rather versatile. This could even be the reason why RNA had to evolve before proteins. Similar principles of biological organisation are reflected in sequence and structure databases of real proteins. Insights gained from modelling are useful for designing more efficient database organisation and search strategies.

Biopolymers↗
PubMed2001

Understanding hierarchical protein evolution from first principles.

We propose a model that explains the hierarchical organization of proteins in fold families. The model, which is based on the evolutionary selection of proteins by their native state stability, reproduces patterns of amino acids conserved across protein families. Due to its dynamic nature, the model sheds light on the evolutionary time-scales. By studying the relaxation of the correlation function between consecutive mutations at a given position in proteins, we observe separation of the evolutionary time-scales: at short time intervals families of proteins with similar sequences and structures are formed, while at long time intervals the families of structurally similar proteins that have low sequence similarity are formed. We discuss the evolutionary implications of our model. We provide a "profile" solution to our model and find agreement between predicted patterns of conserved amino acids and those actually observed in nature.

Amino Acid Sequence↗
PubMed1986

Charge changes in protein evolution.

The number of charge changes relative to total amino acid replacements for each of seven protein sequences (cytochrome c, hemoglobin alpha, hemoglobin beta, myoglobin, insulin, and fibrinopeptides A and B) has been studied. This number was compared with the expected value obtained under the assumption of random nucleotide substitution. The results obtained indicate that four proteins--hemoglobin alpha, hemoglobin beta, myoglobin, and insulin--are accumulating charge changes at rates slower than those predicted by a model of random substitution. Cytochrome c and fibrinopeptides A and B are accumulating charge changes at rates similar to those predicted by a random model.

Animals↗
PubMed1977

[Gene duplication and protein evolution. Case of aminoacyl-t-RNA synthetases].

Aminoacyl-tRNA synthetases are a functionally homologous group of enzymes which catalyse the first step of protein synthesis. The accumulation of data on the oligomeric structures of these enzymes has revealed a wide diversity in the sizes and organization of the protomers. This is not consistent with the idea of a family with homologous primary and tertiary structures. Howewer recent studies have shown that all these enzymes may have evolved from a common ancestor through gene duplication and fusion which has led to extensive repeating sequences in the corresponding subunits.

Amino Acid Sequence↗
PubMed1976

Temperature: a "shaping force' in protein evolution.

1. Comparisons of homologous enzymes from species adapted to widely different temperatures reveal that ligand-binding affinities are rigorously conserved. This is interpreted to mean that a critical relationship between ligand-binding ability and intracellular ligand concentrations must be maintained for proper enzymic regulation. 2. The catalytic efficiencies of enzyme homologues differ in temperature-compensatory manners. Activation free energies are proportional to adaptation temperature and, consequently, low-temperature-adapted enzymes have the highest substrate turnover numbers. 3. Temperature compensatory adjustments in catalytic efficiency may be achieved by altering the number of weak bonds that form or break during a catalytic conformational change. Support for this hypothesis comes from the finding that activation enthalpy and activation entropy values co-vary in a regular manner and by magnitudes consistent with different amounts of weak-bond formation/rupture during catalytic activation in differnt enzyme homologues. 4. Adaptive adjustments in ligand-binding energetics may also involve utilization of the energy changes that occur during conformational changes. This mechanism would permit enzymes with identical binding-site chemistries to display adaptively different ligand affinities. 5. The greater heat-stabilities of enzymes from warm-adapted species may cause these enzymes to be less efficient catalysts than cold-adapted heat-labile enzymes. Heat-stable enzymes may have to break more weak bonds during a catalytic conformational change than do cold-adapted enzymes. The requirements for thermal stability and high catalytic efficiency thus appear to force an adaptational 'compromise'.

Adaptation, Physiological↗
PubMed2002

Accelerated protein evolution and origins of human-specific features: Foxp2 as an example.

Genes responsible for human-specific phenotypes may have been under altered selective pressures in human evolution and thus exhibit changes in substitution rate and pattern at the protein sequence level. Using comparative analysis of human, chimpanzee, and mouse protein sequences, we identified two genes (PRM2 and FOXP2) with significantly enhanced evolutionary rates in the hominid lineage. PRM2 is a histone-like protein essential to spermatogenesis and was previously reported to be a likely target of sexual selection in humans and chimpanzees. FOXP2 is a transcription factor involved in speech and language development. Human FOXP2 experienced a >60-fold increase in substitution rate and incorporated two fixed amino acid changes in a broadly defined transcription suppression domain. A survey of a diverse group of placental mammals reveals the uniqueness of the human FOXP2 sequence and a population genetic analysis indicates possible adaptive selection behind the accelerated evolution. Taken together, our results suggest an important role that FOXP2 may have played in the origin of human speech and demonstrate a strategy for identifying candidate genes underlying the emergences of human-specific features.

Alleles↗
PubMed1997

Prion proteins: evolution and preservation of secondary structure.

Prions cause a variety of neurodegenerative disorders that seem to result from a conformational change in the prion protein (PrP). Thirty-two PrP sequences have been subjected to phylogenetic analysis followed by reconstruction of the most probable evolutionary spectrum of amino acid replacements. The replacement rates suggest that the protein does not seem to be very conservative, but in the course of evolution amino acids have only been substituted within the elements of the secondary structure by those with very similar physico-chemical properties. Analysis of the full spectrum of single-step amino acid substitutions in human PrP using secondary structure prediction algorithms shows an over-representation of substitutions that tend to destabilize alpha-helices.

Amino Acids↗
PubMed2005

In vitro evolutionary thermostabilization of congerin II: a limited reproduction of natural protein evolution by artificial selection pressure.

The thermostability of the conger eel galectin, congerin II, was improved by in vitro evolutionary protein engineering. Two rounds of random PCR mutagenesis and selection experiments increased the congerin II thermostability to a level comparative to its naturally thermostable isoform, congerin I. The crystal structures of the most thermostable double mutant, Y16S/T88I, and the related single mutants, Y16S and T88I, were determined at 2.0 angstroms, 1.8 angstroms, and 1.6 angstroms resolution, respectively. The exclusion of two interior water molecules by the Thr88Ile mutation, and the relief of adjacent conformational stress by the Tyr16Ser mutation were the major contributions to the thermostability. These features in the congerin II mutants are similar to those observed in congerin I. The natural evolution of congerin genes, with the K(A)/K(S) ratio of 2.6, was accelerated under natural selection pressures. The thermostabilizing selection pressure artificially applied to congerin II mimicked the implied natural pressure on congerin I. The results showed that the artificial pressure made congerin II partially reproduce the natural evolution of congerin I.

Amino Acid Sequence↗
PubMed2005

Protein evolution in viral quasispecies under selective pressure: a thermodynamic and phylogenetic analysis.

The evolution of RNA viruses under antiviral pressure is characterized by high mutation rates and strong selective forces that induce extremely rapid changes of protein sequences. This makes the course of molecular evolution directly observable on time scales of months. Here we study the interplay between selection for drug resistance and selection for thermodynamic stability in the protease (PR) and the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) clones extracted from two patients with complex treatment histories. This analysis shows that folding thermodynamic properties may fluctuate very strongly in the course of quasispecies evolution under selective pressure. For the first case, our data suggest that folding efficiency of the RT is sacrificed at the advantage of drug resistance, while the corresponding PR seems to undergo selection for thermodynamic stability in the absence of substitutions associated to resistance. The PR of the second case is not submitted to antiviral pressure during the period analyzed and seems to initiate random fluctuations that lead to the accidental increase of its folding efficiency. In summary, joint consideration of sequence evolution and thermodynamic parameters can represent a more comprehensive approach for the study of the evolution of RNA viruses.

Anti-HIV Agents↗