Research Details
 
Physics and Evolution of Biological Macromolecules
 

Physics and evolution of adaptation to extreme environments

  • Structure 18, 819-828 (2010)
  • Physical Biology 8, 035002 (2011)
  • Nucl. Acids. Res. 42, in press (2014)

We are keen on exploring molecular mechanisms of adaptation and the role of the physics and evolution in selection and tuning of these mechanisms. Specifically, we have developed a model of thermostability in protein complexes (Structure 2010), which describes stabilization if individual domains and interfaces between them along with strengthening mechanisms for prevention of aberrant assemblies. We have shown that thermophilic trends are universal for obligatory and transient complexes and reflect the major physical mechanisms of stability. Further, we have introduced a generalized concept of protein stability, which includes intermolecular interactions that comprise distinct combinations of stabilizing forces depending on the types of interacting partners (Physical Biology 2011). Recently, we have surveyed mechanisms of molecular adaptation based on the physics and evolution of nucleic acids and proteins (NAR 2014). DNA, RNA, and proteins are major biological macromolecules that coevolve and adapt to environments as components of the one highly interconnected system. We have explored sequence/structure determinants of mechanisms of adaptation of these molecules, links between them, and results of their mutual evolution.

The whole picture of molecular mechanisms of adaptation and relations between them is far from being complete. Consideration of different environmental factors such as salinity, pressure, etc. will help us to unravel new mechanisms of stability, their sequence/structure determinants, and to understand tradeoffs that Nature embraced en route of the evolution and adaptation.

 
Evolution of protein function
  • Bioinformatics 26, i497-503 (2010)
  • Bioinformatics 27, 2368-2375 (2011)
  • BMC Evol Biol 12: 75 (2012)

Enzymes are involved in all processes in living organisms, and their contemporary evolution takes place via mutation and recombination of protein (sub)domains. In our recent studies we have considered an enzymatic function as a combination of elementary units that provide elementary chemical transformations. These units are closed loops, possessing one or few functional residues and bringing them to the active site, Elementary Functional Loops (EFLs) (Bioinformatics 2010, 2011). The functions of some EFLs are shared between (super)families of proteins with different biochemical functions and even between different folds. We designed a computational procedure for finding sequence profiles of widely spread EFLs with characteristic functional signatures (Bioinformatics 2010). Further, we developed a procedure for deriving prototypes, which served as basic units of the first folds/domains with enzymatic functions (Bioinformatics 2011). Based on the set of prototypes, knowledge of their elementary functions, and structural contexts, it is possible to represent any enzymatic function as a combination of elementary binding/activation chemical reactions provided by the elementary functional loops. Evolutionary connections between different enzymatic functions can also be delineated (BMC Evol Biol 2012). Figure 1 exemplifies such connections presenting a snapshot of archaeal domain superfamilies organized in a network by prototypes of elementary functions (BMC Evol Biol 2012).

 
Molecular mechanisms of allostery
  • PLoS Comput Biol 7, e1002148 (2011a)
  • PLoS Comput Biol 7, e1002301 (2011b)

Protein function depends on the balance between different conformational states, which can be shifted by many external factors that regulate protein activity including localized perturbations such as ligand binding or post-translational modification. When the perturbation site is not directly adjacent to the site of altered activity the regulation is called allosteric. Recently we introduced two concepts of allosteric regulation and communication. The first concept, binding leverage, allows one to measure the ability of a generic ligand to connect to conformational transitions, and thus its potential to have an allosteric effect (PLoS Comput Biol 2011a). Binding leverage concept of allostery is based on the assumption that binding to sites where ligand-protein interactions are connected to important degrees of freedom can affect the conformational equilibrium between active/inactive states. The second concept, leverage coupling, provides a quantitative characteristic of allosteric communication. The major assumption here is that sites that have high binding leverage for the same motion are more likely to be allosterically coupled than sites that only have high binding leverage for motion along independent degrees of freedom (PLoS Comput Biol 2011b). Figure 2 illustrates work of these concepts by showing functional/allosteric sites and communication between them in phosphofrustokinase (PFK), which is allosterically inhibited by phosphoenolpyruvate (PEP) and activated by ADP binding to the same site.

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