Biomedical subjects

Igor N Berezovsky

Publications and source records attributed to Igor N Berezovsky.

11 recordsLinked to original sources

PubMed2006

Physical origins of protein superfamilies.

In this work, we discovered a fundamental connection between selection for protein stability and emergence of preferred structures of proteins. Using a standard exact three-dimensional lattice model we evolve sequences starting from random ones and determine the exact native structure after each mutation. Acceptance of mutations is biased to select for stable proteins. We found that certain structures, "wonderfolds", are independently discovered numerous times as native states of stable proteins in many unrelated runs of selection. The strong dependence of lattice fold usage on the structural determinant of designability quantitatively reproduces uneven fold usage in natural proteins. Diversity of sequences that fold into wonderfold structures gives rise to superfamilies, i.e. sets of dissimilar sequences that fold into the same or very similar structures. The present work establishes a model of pre-biotic structure selection, which identifies dominant structural patterns emerging upon optimization of proteins for survival in a hot environment. Convergently discovered pre-biotic initial superfamilies with wonderfold structures could have served as a seed for subsequent biological evolution involving gene duplications and divergence.

Amino Acid Sequence↗

PubMed2005

Entropic stabilization of proteins and its proteomic consequences.

Evolutionary traces of thermophilic adaptation are manifest, on the whole-genome level, in compositional biases toward certain types of amino acids. However, it is sometimes difficult to discern their causes without a clear understanding of underlying physical mechanisms of thermal stabilization of proteins. For example, it is well-known that hyperthermophiles feature a greater proportion of charged residues, but, surprisingly, the excess of positively charged residues is almost entirely due to lysines but not arginines in the majority of hyperthermophilic genomes. All-atom simulations show that lysines have a much greater number of accessible rotamers than arginines of similar degree of burial in folded states of proteins. This finding suggests that lysines would preferentially entropically stabilize the native state. Indeed, we show in computational experiments that arginine-to-lysine amino acid substitutions result in noticeable stabilization of proteins. We then hypothesize that if evolution uses this physical mechanism as a complement to electrostatic stabilization in its strategies of thermophilic adaptation, then hyperthermostable organisms would have much greater content of lysines in their proteomes than comparably sized and similarly charged arginines. Consistent with that, high-throughput comparative analysis of complete proteomes shows extremely strong bias toward arginine-to-lysine replacement in hyperthermophilic organisms and overall much greater content of lysines than arginines in hyperthermophiles. This finding cannot be explained by genomic GC compositional biases or by the universal trend of amino acid gain and loss in protein evolution. We discovered here a novel entropic mechanism of protein thermostability due to residual dynamics of rotamer isomerization in native state and demonstrated its immediate proteomic implications. Our study provides an example of how analysis of a fundamental physical mechanism of thermostability helps to resolve a puzzle in comparative genomics as to why amino acid compositions of hyperthermophilic proteomes are significantly biased toward lysines but not similarly charged arginines.

Aminopeptidases↗

PubMed2005

Physics and evolution of thermophilic adaptation.

Analysis of structures and sequences of several hyperthermostable proteins from various sources reveals two major physical mechanisms of their thermostabilization. The first mechanism is "structure-based," whereby some hyperthermostable proteins are significantly more compact than their mesophilic homologues, while no particular interaction type appears to cause stabilization; rather, a sheer number of interactions is responsible for thermostability. Other hyperthermostable proteins employ an alternative, "sequence-based" mechanism of their thermal stabilization. They do not show pronounced structural differences from mesophilic homologues. Rather, a small number of apparently strong interactions is responsible for high thermal stability of these proteins. High-throughput comparative analysis of structures and complete genomes of several hyperthermophilic archaea and bacteria revealed that organisms develop diverse strategies of thermophilic adaptation by using, to a varying degree, two fundamental physical mechanisms of thermostability. The choice of a particular strategy depends on the evolutionary history of an organism. Proteins from organisms that originated in an extreme environment, such as hyperthermophilic archaea (Pyrococcus furiosus), are significantly more compact and more hydrophobic than their mesophilic counterparts. Alternatively, organisms that evolved as mesophiles but later recolonized a hot environment (Thermotoga maritima) relied in their evolutionary strategy of thermophilic adaptation on "sequence-based" mechanism of thermostability. We propose an evolutionary explanation of these differences based on physical concepts of protein designability.

Acclimatization↗

PubMed2004

Universal positions in globular proteins.

The description of globular protein structures as an ensemble of contiguous 'closed loops' or 'tightened end fragments' reveals fold elements crucial for the formation of stable structures and for navigating the very process of protein folding. These are the ends of the loops, which are spatially close to each other but are situated apart in the polypeptide chain by 25-30 residues. They also correlate with the locations of highly conserved hydrophobic residues (referred to as topohydrophobic), in a structural alignment of the members of a protein family. This study analysed these positions in 111 representatives of different protein folds, and then carried out dynamic Monte Carlo simulations of the first steps of the folding process, aimed at predicting the origins of the assembling folds. The simulations demonstrated that there is an obvious trend for certain sets of residues, named 'mostly interacting residues', to be buried at the early stages of the folding process. Location of these residues at the loop ends and correlation with topohydrophobic positions are demonstrated, thereby giving a route to simulations of the protein folding process.

Amino Acid Sequence↗

PubMed2003

Evolutionary aspects of protein structure and folding.

The traditional reconstruction of molecular events of the past based on sequence conservation becomes very vague beyond one to two billion years ago. There are certain molecular features, however, such as polymer flexibility and loop closure, that are conserved merely because of their physical nature. This allows one to penetrate the earliest stages of protein evolution.

Amino Acid Sequence↗

PubMed2003

Protein sequences yield a proteomic code.

Analysis of crystallized protein structures suggests that globular proteins are organized as consecutively connected units of 25-35 residues. These units are closed loops, that is returns of the polypeptide chain trajectory to a close contact with itself. This universal feature of apparently polymer-statistical nature is a basis for a principally novel view on the globular proteins as loop fold structures. The same unit size has been detected in protein sequences translated from complete prokaryotic genomes by positional autocorrelation analysis, which strongly indicates the evolutionary connection of the units. The units are further characterized by prototype sequences matching to their numerous derivatives in the translated genomes. The matches to five strongest prokaryotic prototypes and three prototypes of C. elegans are identified in the sequences of crystallized proteins, and their structures analyzed. Corresponding segments of the polypeptide chains in majority of cases form closed loops, though evolutionary fate of every prototype element is shown to be rather diverse. Then loop ends can be separated by a sequence-wise distant segments and stabilized by the spatial interactions in the context of the overall globular structure. The units belong to a presumably limited spectrum of the sequence prototypes, full repertoire of which would constitute a proteomic code.

Amino Acid Motifs↗

PubMed2003

Spelling protein structure.

Recent sequence analysis of complete prokaryotic proteomes suggests that in early evolutionary stages proteins were rather small, of the size 25-35 amino acids. Corroborating evidence comes from protein crystal data, which indicate this size for closed loops--universal structural units of globular proteins. In the latest development we were able to derive and structurally characterize several sequence/structure prototypes apparently representing early protein units. Structurally the prototypes appear as closed loops stabilized by end-to-end van der Waals interactions. While nearly standard in size the loops are highly diverse in terms of their secondary structure. A presentation of the protein as an assembly of descendants of the prototypes, the first of its kind, is described in detail here. The sequence and structure of the ATP-binding subunit of histidine permease of S. typhimurium is shown to contain several modified copies of different prototype elements, closed loops, and, thus, can be spelled as: x-PI-x-PIV-PVI-PII-PVII-x, where PI-PVII are the prototype elements. This study sets up the basic principles for the sequence/structure prototype spelling of globular proteins.

ATP-Binding Cassette Transporters↗

PubMed2003

Discrete structure of van der Waals domains in globular proteins.

Most globular proteins are divisible by domains, distinct substructures of the globule. The notion of hierarchy of the domains was introduced earlier via van der Waals energy profiles that allow one to subdivide the proteins into domains (subdomains). The question remains open as to what is the possible structural connection of the energy profiles. The recent discovery of the loop-n-lock elements in the globular proteins suggests such a structural connection. A direct comparison of the segmentation by van der Waals energy criteria with the maps of the locked loops of nearly standard size reveals a striking correlation: domains in general appear to consist of one to several such loops. In addition, it was demonstrated that a variety of subdivisions of the same protein into domains is just a regrouping of the loop-n-lock elements.

Protein Conformation↗

PubMed2002

Loop fold structure of proteins: resolution of Levinthas paradox.

According to Levinthal a protein chain of ordinary size would require enormous time to sort its conformational states before the final fold is reached. Experimentally observed time of folding suggests an estimate of the chain length for which the time would be sufficient. This estimate by order of magnitude fits to experimentally observed universal closed loop elements of globular proteins - 25-30 residues.

Models, Chemical↗

PubMed2002

Back to units of protein folding.

In response to the criticism by A. Finkelstein (J Biomol Struct Dyn 20, 311-314, 2002) of our Communication (J Biomol Struct Dyn 20, 5-6, 2002) several issues are dealt with. Importance of the notion of elementary folding unit, its size and structure, and the necessity of further characterization of the units for the elucidation of the protein folding in vivo are discussed. The criticism (J Biomol Struct Dyn 20, 311-314, 2002) on the hierarchical protein folding is also briefly addressed.

Kinetics↗

PubMed2002

Closed loops: persistence of the protein chain returns.

It has recently been discovered that globular proteins are universally built from standard loop-n-lock units of about 30 amino acid residues. The hypothesis has been put forward on the loop stage in the protein evolution when the units were autonomous. Later they joined together making longer chains. One would expect that the early individual loop-n-lock elements might still be detected in modern protein sequences as remnants of the hypothetical 30-residue sequence prototypes. Among several strong sequence motifs, extracted from protein sequences of 23 complete bacterial proteomes, one 32-residue prototype was studied here in detail. Numerous sequence segments related to the prototype are identified in the crystal structures of proteins of a PDB_SELECT database. Analysis of the respective chain trajectories for the cases with different degrees of sequence conservation confirms that the majority of the segments correspond to the closed loops. In the evolutionary diversification of the prototypes the secondary structure yields first, while the sequence is still moderately conserved. The last feature to go is the chain return property. Apparently, the opening of the loops would severely destabilize the protein fold, which explains their conservation.

Amino Acid Motifs↗