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Physics and physicists in Biology: 50 years in Armenia Y. Mamasakhlisov, Yerevan State University Tbilisi, Macrh 14-15, 2013 Beginning • The Department of Molecular Physics (before 1992 Department of Molecular Physics and Biophysics) was formed in the Physical Department of YSU at 1967 owing to the efforts of doctor of phys-math sci., professor. Vilen.M.Aslanian, who was a disciple of Leningrad School of Physics of Macromolecules (M.V.Volkenstein). It also has predetermined the main scientific direction of the Department - research of structure of synthetic and biological (DNA, RNA, proteins, membranes) macromolecules - which is kept to this day. • The Department of Biophysics was established in 1963. The founder and the first Chair of the Department was Professor Gerasim H.Panosyan. The Department of Molecular Physics: people The Department of Molecular Physics: students and teaching • 10-15 bachelors • 5-7 masters • Courses: statistical physics of macromolecules, physics of membranes, non-equilibrium thermodynamics, physics of nucleic acids, protein folding, molecular spectroscopy etc. Events Our friends in theory • • • • Ananikyan Nerses Allahverdyan Armen Nersessian Armen etc. Main directions I. Helical structures formation Main directions II. DNA, RNA ligand complexes Helical structures and exactly solvable models N H J i 2 ,1 i 1 ,1 i ,1 i 1 N H J 0 N () , 1 J i i k i 1 k 1 i 1 Model parameters: • The energy U of hydrogen bond formation • The discrete number Q of possible conformations of each repeated unit • Number of repeated units, fixed by one hydrogen bond. 1d Potts and GMPC N H J 0 N () , 1 J i i k i 1 k 1 i 1 H PM J ( i , j ) ij Main directions. III • • • • RNA and protein folding Electrostatic effects DNA condensation Physics of membranes, etc. dsDNA transition from the stretched to condensed conformation. dsDNA stretching experiment in presence of condensing agents. I. G Lf dsDNA stretching experiment in presence of condensing agents. II. B.A.Todd and D.C. Rau, Nucl. Acids Res., 36, 501 (2008). B.A.Todd, et al., Biophys. J., 94, 4775 (2008). The comparison between theory and experiment Phys. Rev. E, 80, 031915 (2009). RNA folding: the different stability of secondary and tertiary structures. • Catalytically active RNAs are largely preorganized for substrate binding and catalysis, much like a typical protein enzyme. Like proteins and DNA, the biological function of the RNA molecule in living organisms depends on its specific folded spatial structures. Secondary and tertiary structure of RNA … AUUGGCCCUAUAUAUUUU … (4 letters) Motivation • Large ribozymes exhibit very slow folding results from the formation of kinetically trapped, misfolded intermediates (Treiber, and Williamson, Curr. Opinion. Struct. Biol. (1991)). • The folding landscape of the Tetrahymena ribozyme contains discrete folding pathways, separated by free energy barriers. A specific long-range tertiary contacts have a strong influence on the folding process (R. Russel et al., (2002)) • The P5abc subdomain of the Tetrahymena ribozyme folds into a tertiary structure with greatly changed base pairing, consistent with crystal structure (Wu, and Tinoco, (1998) ). • RNA secondary structure is characterized by a rugged energy landscape with many alternative local minima. Several features are observed that are qualitatively similar to the replica theory of spin glasses. (Higgs, PRL (1996)). How is necessary to consider RNA secondary and tertiary structures separately? The glassy and melting temperatures Tm ln Tfr. 2S ln 2 ln 1 1 ~ I Phys. Rev. E, 75, 061907 (2007). The higher stability of the secondary structure is not necessarily caused by higher energy of interaction, but can have entopic nature Tfr. Tm The logarithmic dependence of the melting temperature on the ionic strength of solvent Tm ln Shiman and Draper, JMB (2000) ~ I 1 Protein folding problem … AABGLLILCSDDFAGAA … (20 letters) Protein folding and the statistical features of amino acids sequences The electrostatic interactions between macroions and the different timescales of relaxation. • Interaction of charged macromolecules (macroions) is essential for soft and biological materials in order to maintain their complex structure and distinct functioning. In many cases, charge patterns along macromolecular surfaces are inhomogeneous and exhibit a highly disordered spatial distribution. DNA microarrays, surfactantcoated surfaces, random polyelectrolytes and polyampholytes present examples of such disordered charge distributions. • The charge pattern can be either set and quenched in the process of assembly of these surfaces, or can exhibit various degrees of annealing when interacting with other macromolecules in aqueous solutions. Disorder annealing in charged systems may result from different sources; e.g., finite mobility and mixing of charged units (lipids and proteins) in lipid membranes, conformational rearrangement of DNA chains in DNA microarrays and charge regulation of contact surfaces bearing weak acidic groups in aqueous solutions. For example … Gene chips Surface covered by surfactants Random polyelectrolites and polyampolites The characteristic time scales • The coefficient of lateral diffusion of phospholipids in membrane (Alberts et al., 2002) 2 cm ~ 10 8 sec • The coefficient of diffusion of metal ions in water solution (Kariuki, Dewald, 1995) 2 cm ~ 10 5 sec Two – temperature dynamics • The system of macroions with partially “annealed" distribution of the surface charge and free Z - valent counterions at the temperature T . The surface charges can have the effective temperature T , non equal to T , because of their slow in comparison with fast relaxing counterions dynamics. The mean - field approximation Z D W Z ci In the mean – field (Poisson – Boltzmann) approximation obtaining … Z ci ~ D e The renormalized surface charge density is always lower than bar mean value . Thus, partially annealed disorder is effectively neutralize the surface charge. ng Z H , n Taking into account fluctuations: the strong couple limit • The Poisson – Boltzmann approximation is adequate only for the monovalent cations or the high temperatures. We need to take into account the influence of fluctuations for multyvalent cations. • The asymptotically exact strong - coupling theory (SC) can be obtained in terms of virial expansion over the powers of counter-ions fugacity (Netz, 2001) Z Z 0 Z1 2 The instability and the system collapse (instead of Summary) • The contribution of the quenched disorder results to the continuous collapse transition at the threshold value c 1 . The optimal inter – surface distance behaves as: 2 1 ( 1) 0 ( 1) d0 • The partially annealed disorder gives the following inter - surface distance: 2 1 4 d 0 1 0 ( 1) ( 1) • The system collapses independently of the values of other parameters in absence of salt ( 0). RNA secondary structure Vienna package • RNAheat • RNAfold McCaskill algorithm • (Waterman and Smith (1986); McCaskill (1990); Zuker et al. (1991); Hofacker et al. (1994)) Specific heat vs. temperature (attraction+repulsion) A A U U S CV T T Collaborators: • • • • • • V. Morozov (YSU, Yerevan, Armenia) A. Badasyan (Univ. Ca’Foscari, Venice, Italy) A. Parsegian (UMass, USA) B. Todd (Purdue Univ., USA) R. Podgornik (University of Ljubljana, Slovenia) A. Naji (Institute for Research in Fundamental Sciences, Tehran, Iran) • A. Nersessian (YSU, Yerevan, Armenia) Thank you