352 research outputs found
Pump-probe polarized transient hole burning (PTHB) dynamics of hydrated electron revisited
Femtosecond PTHB spectroscopy was expected to demonstrate the existence of
distinct s-p absorption subbands originating from the three nondegenerate
p-like excited states of hydrated electron in anisotropic solvation cavity. Yet
no conclusive experimental evidence either for this subband structure or the
reorientation of the cavity on the picosecond time scale has been obtained. We
demonstrate that rapid reorientation of s-p transition dipole moments in
response to small scale motion of water molecules is the likely culprit. The
polarized bleach is shown to be too small and too short lived to be observed
reliably on the sub-picosecond time scale.Comment: 10 pages + 3 figures + supplement, will be submitted shortly to Chem.
Phys. Let
Sequence Dependence of Self-Interacting Random Chains
We study the thermodynamic behavior of the random chain model proposed by
Iori, Marinari and Parisi, and how this depends on the actual sequence of
interactions along the chain. The properties of randomly chosen sequences are
compared to those of designed ones, obtained through a simulated annealing
procedure in sequence space. We show that the transition to the folded phase
takes place at a smaller strength of the quenched disorder for designed
sequences. As a result, folding can be relatively fast for these sequences.Comment: 14 pages, uuencoded compressed postscript fil
Hydrophobic and ionic-interactions in bulk and confined water with implications for collapse and folding of proteins
Water and water-mediated interactions determine thermodynamic and kinetics of
protein folding, protein aggregation and self-assembly in confined spaces. To
obtain insights into the role of water in the context of folding problems, we
describe computer simulations of a few related model systems. The dynamics of
collapse of eicosane shows that upon expulsion of water the linear hydrocarbon
chain adopts an ordered helical hairpin structure with 1.5 turns. The structure
of dimer of eicosane molecules has two well ordered helical hairpins that are
stacked perpendicular to each other. As a prelude to studying folding in
confined spaces we used simulations to understand changes in hydrophobic and
ionic interactions in nano droplets. Solvation of hydrophobic and charged
species change drastically in nano water droplets. Hydrophobic species are
localized at the boundary. The tendency of ions to be at the boundary where
water density is low increases as the charge density decreases. Interaction
between hydrophobic, polar, and charged residue are also profoundly altered in
confined spaces. Using the results of computer simulations and accounting for
loss of chain entropy upon confinement we argue and then demonstrate, using
simulations in explicit water, that ordered states of generic amphiphilic
peptide sequences should be stabilized in cylindrical nanopores
Design of HIV-1-PR inhibitors which do not create resistance: blocking the folding of single monomers
One of the main problems of drug design is that of optimizing the
drug--target interaction. In the case in which the target is a viral protein
displaying a high mutation rate, a second problem arises, namely the eventual
development of resistance. We wish to suggest a scheme for the design of
non--conventional drugs which do not face any of these problems and apply it to
the case of HIV--1 protease. It is based on the knowledge that the folding of
single--domain proteins, like e.g. each of the monomers forming the HIV--1--PR
homodimer, is controlled by local elementary structures (LES), stabilized by
local contacts among hydrophobic, strongly interacting and highly conserved
amino acids which play a central role in the folding process. Because LES have
evolved over myriads of generations to recognize and strongly interact with
each other so as to make the protein fold fast as well as to avoid aggregation
with other proteins, highly specific (and thus little toxic) as well as
effective folding--inhibitor drugs suggest themselves: short peptides (or
eventually their mimetic molecules), displaying the same amino acid sequence of
that of LES (p--LES). Aside from being specific and efficient, these inhibitors
are expected not to induce resistance: in fact, mutations which successfully
avoid their action imply the destabilization of one or more LES and thus should
lead to protein denaturation. Making use of Monte Carlo simulations within the
framework of a simple although not oversimplified model, which is able to
reproduce the main thermodynamic as well as dynamic properties of monoglobular
proteins, we first identify the LES of the HIV--1--PR and then show that the
corresponding p--LES peptides act as effective inhibitors of the folding of the
protease which do not create resistance
Fluctuations of water near extended hydrophobic and hydrophilic surfaces
We use molecular dynamics simulations of the SPC-E model of liquid water to
derive probability distributions for water density fluctuations in probe
volumes of different shapes and sizes, both in the bulk as well as near
hydrophobic and hydrophilic surfaces. To obtain our results, we introduce a
biased sampling of coarse-grained densities, which in turn biases the actual
solvent density. The technique is easily combined with molecular dynamics
integration algorithms. Our principal result is that the probability for
density fluctuations of water near a hydrophobic surface, with or without
surface-water attractions, is akin to density fluctuations at the water-vapor
interface. Specifically, the probability of density depletion near the surface
is significantly larger than that in bulk. In contrast, we find that the
statistics of water density fluctuations near a model hydrophilic surface are
similar to that in the bulk
FIEFDom: a transparent domain boundary recognition system using a fuzzy mean operator
Protein domain prediction is often the preliminary step in both experimental and computational protein research. Here we present a new method to predict the domain boundaries of a multidomain protein from its amino acid sequence using a fuzzy mean operator. Using the nr-sequence database together with a reference protein set (RPS) containing known domain boundaries, the operator is used to assign a likelihood value for each residue of the query sequence as belonging to a domain boundary. This procedure robustly identifies contiguous boundary regions. For a dataset with a maximum sequence identity of 30%, the average domain prediction accuracy of our method is 97% for one domain proteins and 58% for multidomain proteins. The presented model is capable of using new sequence/structure information without re-parameterization after each RPS update. When tested on a current database using a four year old RPS and on a database that contains different domain definitions than those used to train the models, our method consistently yielded the same accuracy while two other published methods did not. A comparison with other domain prediction methods used in the CASP7 competition indicates that our method performs better than existing sequence-based methods
Visualization of Early Events in Acetic Acid Denaturation of HIV-1 Protease: A Molecular Dynamics Study
Protein denaturation plays a crucial role in cellular processes. In this study, denaturation of HIV-1 Protease (PR) was investigated by all-atom MD simulations in explicit solvent. The PR dimer and monomer were simulated separately in 9 M acetic acid (9 M AcOH) solution and water to study the denaturation process of PR in acetic acid environment. Direct visualization of the denaturation dynamics that is readily available from such simulations has been presented. Our simulations in 9 M AcOH reveal that the PR denaturation begins by separation of dimer into intact monomers and it is only after this separation that the monomer units start denaturing. The denaturation of the monomers is flagged off by the loss of crucial interactions between the α-helix at C-terminal and surrounding β-strands. This causes the structure to transit from the equilibrium dynamics to random non-equilibrating dynamics. Residence time calculations indicate that denaturation occurs via direct interaction of the acetic acid molecules with certain regions of the protein in 9 M AcOH. All these observations have helped to decipher a picture of the early events in acetic acid denaturation of PR and have illustrated that the α-helix and the β-sheet at the C-terminus of a native and functional PR dimer should maintain both the stability and the function of the enzyme and thus present newer targets for blocking PR function
Molecular Dynamics Simulation Study of Interaction between Model Rough Hydrophobic Surfaces
We study some aspects of hydrophobic interaction between molecular rough and
flexible model surfaces. The model we use in this work is based on a model we
used previously (Eun, C.; Berkowitz, M. L. J. Phys. Chem. B 2009, 113,
13222-13228), when we studied the interaction between model patches of lipid
membranes. Our original model consisted of two graphene plates with attached
polar headgroups; the plates were immersed in a water bath. The interaction
between such plates can be considered as an example of a hydrophilic
interaction. In the present work we modify our previous model by removing the
charge from the zwitterionic headgroups. As a result of this procedure, the
plate character changes; it becomes hydrophobic. By separating the total
interaction (or potential of mean force, PMF) between plates into the direct
and the water-mediated interactions we observe that the latter changes from
repulsive to attractive, clearly emphasizing the important role of water as a
medium. We also investigate the effect of roughness and flexibility of the
headgroups on the interaction between plates and observe that roughness
enhances the character of the hydrophobic interaction. The presence of a
dewetting transition in a confined space between charge-removed plates confirms
that the interaction between plates is strongly hydrophobic. In addition, we
notice that there is a shallow local minimum in the PMF in case of
charge-removed plates. We find that this minimum is associated with the
configurational changes that flexible headgroups undergo, as the two plates are
brought together.Comment: 27 pages, 9 figure
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