12 research outputs found
The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein
The folding pathway and rate coefficients of the folding of a knotted protein
are calculated for a potential energy function with minimal energetic
frustration. A kinetic transition network is constructed using the discrete
path sampling approach, and the resulting potential energy surface is
visualized by constructing disconnectivity graphs. Owing to topological
constraints, the low-lying portion of the landscape consists of three distinct
regions, corresponding to the native knotted state and to configurations where
either the N- or C-terminus is not yet folded into the knot. The fastest
folding pathways from denatured states exhibit early formation of the
N-terminus portion of the knot and a rate-determining step where the C-terminus
is incorporated. The low-lying minima with the N-terminus knotted and the
C-terminus free therefore constitute an off-pathway intermediate for this
model. The insertion of both the N- and C-termini into the knot occur late in
the folding process, creating large energy barriers that are the rate limiting
steps in the folding process. When compared to other protein folding proteins
of a similar length, this system folds over six orders of magnitude more
slowly.Comment: 19 page
Exploring the Free Energy Landscape: From Dynamics to Networks and Back
The knowledge of the Free Energy Landscape topology is the essential key to
understand many biochemical processes. The determination of the conformers of a
protein and their basins of attraction takes a central role for studying
molecular isomerization reactions. In this work, we present a novel framework
to unveil the features of a Free Energy Landscape answering questions such as
how many meta-stable conformers are, how the hierarchical relationship among
them is, or what the structure and kinetics of the transition paths are.
Exploring the landscape by molecular dynamics simulations, the microscopic data
of the trajectory are encoded into a Conformational Markov Network. The
structure of this graph reveals the regions of the conformational space
corresponding to the basins of attraction. In addition, handling the
Conformational Markov Network, relevant kinetic magnitudes as dwell times or
rate constants, and the hierarchical relationship among basins, complete the
global picture of the landscape. We show the power of the analysis studying a
toy model of a funnel-like potential and computing efficiently the conformers
of a short peptide, the dialanine, paving the way to a systematic study of the
Free Energy Landscape in large peptides.Comment: PLoS Computational Biology (in press
An ab initio and AIM investigation into the hydration of 2-thioxanthine
<p>Abstract</p> <p>Background</p> <p>Hydration is a universal phenomenon in nature. The interactions between biomolecules and water of hydration play a pivotal role in molecular biology. 2-Thioxanthine (2TX), a thio-modified nucleic acid base, is of significant interest as a DNA inhibitor yet its interactions with hydration water have not been investigated either computationally or experimentally. Here in, we reported an <it>ab initio </it>study of the hydration of 2TX, revealing water can form seven hydrated complexes.</p> <p>Results</p> <p>Hydrogen-bond (H-bond) interactions in 1:1 complexes of 2TX with water are studied at the MP2/6-311G(d, p) and B3LYP/6-311G(d, p) levels. Seven 2TX<sup>...</sup>H<sub>2</sub>O hydrogen bonded complexes have been theoretically identified and reported for the first time. The proton affinities (PAs) of the O, S, and N atoms and deprotonantion enthalpies (DPEs) of different N-H bonds in 2TX are calculated, factors surrounding why the seven complexes have different hydrogen bond energies are discussed. The theoretical infrared and NMR spectra of hydrated 2TX complexes are reported to probe the characteristics of the proposed H-bonds. An improper blue-shifting H-bond with a shortened C-H bond was found in one case. NBO and AIM analysis were carried out to explain the formation of improper blue-shifting H-bonds, and the H-bonding characteristics are discussed.</p> <p>Conclusion</p> <p>2TX can interact with water by five different H-bonding regimes, N-H<sup>...</sup>O, O-H<sup>...</sup>N, O-H<sup>...</sup>O, O-H<sup>...</sup>S and C-H<sup>...</sup>O, all of which are medium strength hydrogen bonds. The most stable H-bond complex has a closed structure with two hydrogen bonds (N(7)-H<sup>...</sup>O and O-H<sup>...</sup>O), whereas the least stable one has an open structure with one H-bond. The interaction energies of the studied complexes are correlated to the PA and DPE involved in H-bond formation. After formation of H-bonds, the calculated IR and NMR spectra of the 2TX-water complexes change greatly, which serves to identify the hydration of 2TX.</p
Gas-Phase IR Spectroscopy of Nucleobases.
IR spectroscopy of nucleobases in the gas phase reflects simultaneous advances in both experimental and computational techniques. Important properties, such as excited state dynamics, depend in subtle ways on structure variations, which can be followed by their infrared signatures. Isomer specific spectroscopy is a particularly powerful tool for studying the effects of nucleobase tautomeric form and base pair hydrogen-bonding patterns
UV-excitation from an experimental perspective: frequency resolved.
Electronic spectroscopy of DNA bases in the gas phase provides detailed information about the electronic excitation, which places the molecule in the Franck-Condon region in the excited state and thus prepares the starting conditions for excited-state dynamics. Double resonance or hole-burning spectroscopy in the gas phase can provide such information with isomer specificity, probing the starting potential energy landscape as a function of tautomeric form, isomeric structure, or hydrogen bonded or stacked cluster structure. Action spectroscopy, such REMPI, can be affected by excited-state lifetimes