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1. Protein-Protein and Protein-Drug interactions
1. Protein-Protein and Protein-Drug interactions
2. Potential of Mean Force reconstruction
2. Potential of Mean Force reconstruction
The PMF(free energy) reconstruction is one of the most expensive tasks in computational chemistry and molecular biology. The problem stems from the dissipation generated during the perturbation. In 1997 C. Jarzynski presented a new theoretical framework able to directly connect the free energy difference and the external work, even with a far from equilibrium perturbations. The drawback of this relation is the number of work samples (perturbation trajectories) required to calculate a satisfying PMF estimate. I focused my research on the development of new perturbation schemes able to decrease the number of work trajectories required for an acceptable PMF reconstruction.
Project details:
Project details:
The idea was to develop protocols applicable with both simulations and real-world molecule manipulation techniques.
The theoretical work, development and testing was performed using a simplified Brownian motion framework. The detailed study was done using the molecular dynamics simulation package NAMD.
The both set of experiments simulated the polymer stretching as performed by AFM (Atomic Force Microscopy), therefore
Some of the protocols are directly applicable with real-world molecule manipulation apparatuses.
I wrote the Brownian motion simulation and the PMF reconstruction code (for both MD and Brownian simulations) in C++ and Matlab. The control routines for NAMD were written in Tcl/Tk.
3. Chromatin structure modeling
3. Chromatin structure modeling
The universe (which others call the Library) is composed of an indefinite and perhaps infinite number of hexagonal galleries, with vast air shafts between, surrounded by very low railings. From any of the hexagons one can see, interminably, the upper and lower floors. The distribution of the galleries is invariable. Twenty shelves, five long shelves per side, cover all the sides except two; their height, which is the distance from floor to ceiling, scarcely exceeds that of a normal bookcase. One of the free sides leads to a narrow hallway which opens onto another gallery, identical to the first and to all the rest. To the left and right of the hallway there are two very small closets. In the first, one may sleep standing up; in the other, satisfy one's fecal necessities. Also through here passes a spiral stairway, which sinks abysmally and soars upwards to remote distances. In the hallway there is a mirror which faithfully duplicates all appearances. Men usually infer from this mirror that the Library is not infinite (if it were, why this illusory duplication?); I prefer to dream that its polished surfaces represent and promise the infinite ... Light is provided by some spherical fruit which bear the name of lamps. There are two, transversally placed, in each hexagon. The light they emit is insufficient, incessant.
Like all men of the Library, I have traveled in my youth; I have wandered in search of a book, perhaps the catalogue of catalogues; now that my eyes can hardly decipher what I write, I am preparing to die just a few leagues from the hexagon in which I was born. Once I am dead, there will be no lack of pious hands to throw me over the railing; my grave will be the fathomless air; my body will sink endlessly and decay and dissolve in the wind generated by the fall, which is infinite. I say that the Library is unending. The idealists argue that the hexagonal rooms are a necessary form of absolute space or, at least, of our intuition of space. They reason that a triangular or pentagonal room is inconceivable. (The mystics claim that their ecstasy reveals to them a circular chamber containing a great circular book, whose spine is continuous and which follows the complete circle of the walls; but their testimony is suspect; their words, obscure. This cyclical book is God.) Let it suffice now for me to repeat the classic dictum: The Library is a sphere whose exact center is any one of its hexagons and whose circumference is inaccessible.
Jorge Luis Borges
"The Library of Babel"
Figure 1. Chromatin as an infinite library
On the left is the labyrinth from the Umberto Eco's novel " The Name of the Rose", and on the right are chromatin structures based on different nucleosome repeat lengths (173, 182, 191 and 200 DNA base pairs). Numbers in brackets are lengths of DNA linkers connecting individual nucleosomes, expressed as DNA base pairs. Odd and even nucleosomes are colored white and navy blue, respectively. Linker histones and nucleosome tails are not visualized, although they are represented in the coarse grained chromatin model. This research was done in collaboration with Dr. Tamar Schlick from New York University.
I used fragment from J.L. Borge's short story The Library of Babel because I see the Universe/Library in his story as a metaphorical description of chromatin. I mentioned "The Name of the Rose" because Eco was (partly) inspired by this Borge's story. The labyrinth in his novel reminds me of DNA.
4. Mechanical properties of proteins
4. Mechanical properties of proteins
I am interested in the behavior of proteins with known mechanical role (spectrin), or proteins with exceptional thermodynamical stability (Top7). That research is fueled by my interest in the design of nanoscale objects with predetermined mechanical roles.
Figure 2. Top7 structure
The distribution of the hydrogen bonds belonging to the Top7's β sheet. Dashed, colored lines are hydrogen bonds. Superficially, Top7 is structurally symmetric. Stretching reveals the dis-balance and the true resistance mechanism which lies hidden below the hydrogen bonds.
Figure 3. Top7 stretching simulation
The conformation of the protein after it had been pulled for 50 Å.
Force-extension diagram.
The number (moving average) of hydrogen bonds belonging to the β sheet during the pulling. The force peak is connected to the behavior of the second group (green set) of hydrogen bonds.
The distribution of hydrophobic residues corresponds to the Top7's unfolding pattern (regardless if it is being stretched from N terminus or from C terminus). Nonbonded interactions guide protein through the unfolding landscape; the protein backbone and hydrogen bonds are just a skeleton.
Figure 4. Spectrin interface behavior during simulated streching
The stretching of the wild-type and mutated erythroid spectrin interfaces using constant pulling velocity. The mutated interfaces were modeled following the assumption that they resemble regular spectrin triple-helical repeats. Monomers first unfold and then start to unbind. Some of the mutants exhibit higher unfolding forces which may imply that they possess higher binding energy barriers than the wild type interface(s).
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