5 research outputs found
Fe(II)/Fe(III) Redox Process Can Significantly Modulate the Conformational Dynamics and Electrostatics of Pirin in NF-ĪŗB Regulation
Pirin is an iron (Fe)-dependent regulatory
protein of nuclear factor
ĪŗB (NF-ĪŗB) transcription factors. Binding studies have
suggested that the oxidative state of iron plays a crucial role in
modulating the binding of Pirin to NF-ĪŗB p65, in turn enhancing
the binding of p65 to DNA. The FeĀ(III) form of Pirin is the active
form and binds to NF-ĪŗB, whereas the FeĀ(II) form does not bind
to NF-ĪŗB. However, the surprising consequence of a single charge
perturbation in the functional modulation of NF-ĪŗB is not well
understood. Here, we use quantum mechanical calculations and microsecond-long
molecular dynamics simulations to explore the free-energy landscapes
of the FeĀ(II) and FeĀ(III) forms of Pirin. We show that the restricted
conformational space and electrostatic complementarity of the FeĀ(III)
form of Pirin are crucial for binding and regulation of NF-ĪŗB.
Our results suggest that a subtle single-electron redox trigger could
significantly modulate the conformational dynamics and electrostatics
of proteins in subcellular allosteric regulatory processes
Coupled Dynamics and Entropic Contribution to the Allosteric Mechanism of Pin1
Allosteric communication
in proteins regulates a plethora of downstream
processes in subcellular signaling pathways. Describing the effects
of cooperative ligand binding on the atomic level is a key to understanding
many regulatory processes involving biomolecules. Here, we use microsecond-long
molecular dynamics simulations to investigate the allosteric mechanism
of Pin1, a potential therapeutic target and a phosphorylated-Ser/Thr
dependent peptidyl-prolyl <i>cis</i>ā<i>trans</i> isomerase that regulates several subcellular processes and has been
implicated in many diseases, including cancer and Alzheimerās.
Experimental studies suggest that the catalytic domain and the noncatalytic
WW domain are allosterically coupled; however, an atomic level description
of the dynamics associated with the interdomain communication is lacking.
We show that binding of the substrate to the WW domain is directly
coupled to the dynamics of the catalytic domain, causing rearrangement
of the residueāresidue contact dynamics from the WW domain
to the catalytic domain. The binding affinity of the substrate in
the catalytic domain is also enhanced upon binding of the substrate
to the WW domain. Modulation of the dynamics of the catalytic domain
upon binding of the substrate to the WW domain leads to prepayment
of the entropic cost of binding the substrate to the catalytic domain.
This study shows that Ile 28 at the interfacial region between the
catalytic and WW domains is certainly one of the residues responsible
for bridging the communication between the two domains. The results
complement previous experiments and provide valuable atomistic insights
into the role of dynamics and possible entropic contribution to the
allosteric mechanism of proteins
Hydrocarbons Depending on the Chain Length and Head Group Adopt Different Conformations within a Water-Soluble Nanocapsule: <sup>1</sup>H NMR and Molecular Dynamics Studies
In this study we have examined the conformational preference
of
phenyl-substituted hydrocarbons (alkanes, alkenes, and alkynes) of
different chain lengths included within a confined space provided
by a molecular capsule made of two host cavitands known by the trivial
name āocta acidā (OA). One- and two-dimensional <sup>1</sup>H NMR experiments and molecular dynamics (MD) simulations
were employed to probe the location and conformation of hydrocarbons
within the OA capsule. In general, small hydrocarbons adopted a linear
conformation while longer ones preferred a folded conformation. In
addition, the extent of folding and the location of the end groups
(methyl and phenyl) were dependent on the group (H<sub>2</sub>CāCH<sub>2</sub>, HCī»CH, and Cī¼C) adjacent to the phenyl group.
In addition, the rotational mobility of the hydrocarbons within the
capsule varied; for example, while phenylated alkanes tumbled freely,
phenylated alkenes and alkynes resisted such a motion at room temperature.
Combined NMR and MD simulation studies have confirmed that molecules
could adopt conformations within confined spaces different from that
in solution, opening opportunities to modulate chemical behavior of
guest molecules
Comparative molecular dynamics simulation studies for determining factors contributing to the thermostability of chemotaxis protein āCheYā
<div><p>Comparative molecular dynamics simulations of chemotaxis protein āCheYā from thermophilic origin <i>Thermotoga maritima</i> and its mesophilic counterpart <i>Salmonella enterica</i> have been performed for 10āns each at 300 and 350āK, and 20āns each at 400 and 450āK. The trajectories were analyzed in terms of different factors like root-mean-square deviation, root-mean-square fluctuation, radius of gyration, solvent accessible surface area, H-bonds, salt bridge content, and proteināsolvent interactions which indicate distinct differences between the two of them. The two proteins also follow dissimilar unfolding pathways. The overall flexibility calculated by the trace of the diagonalized covariance matrix displays similar flexibility of both the proteins near their optimum growth temperatures. However, at higher temperatures mesophilic protein shows increased overall flexibility than its thermophilic counterpart. Principal component analysis also indicates that the essential subspaces explored by the simulations of two proteins at different temperatures are nonoverlapping and they show significantly different directions of motion. However, there are significant overlaps within the trajectories and similar direction of motions are observed for both proteins at 300āK. Overall, the mesophilic protein leads to increased conformational sampling of the phase space than its thermophilic counterpart. This is the first ever study of thermostability of CheY protein homologs by using protein dynamism as a main impact. Our study might be used as a model for studying the molecular basis of thermostability of two homologous proteins from two organisms living at different temperatures with less visible differences.</p></div
Dimerization of the Full-Length Alzheimer Amyloid Ī²-Peptide (AĪ²42) in Explicit Aqueous Solution: A Molecular Dynamics Study
In this study, the mechanism of dimerization of the full-length
Alzheimer amyloid beta (AĪ²42) peptide and structural properties
of the three most stable dimers have been elucidated through 0.8 Ī¼s
classical molecular dynamics (MD) simulations. The AĪ²42 dimer
has been reported to be the smallest neurotoxic species that adversely
affects both memory and synaptic plasticity. On the basis of interactions
between the distinct regions of the AĪ²42 monomer, 10 different
starting configurations were developed from their native folded structures.
However, only six of them were found to form dimers and among them
the three most stable (<b>X</b><sup><b>P</b></sup>, <b>C</b>ā<b>C</b><sup><b>AP</b></sup>, and <b>N</b>ā<b>N</b><sup><b>P</b></sup>) were chosen
for the detailed analysis. The structural properties of these dimers
were compared with the available experimental and theoretical data.
The MD simulations show that hydrophobic regions of both monomers
play critical roles in the dimerization process. The high content
of the Ī±-helical structure in all the dimers is in line with
its experimentally proposed role in the oligomerization. The formation
of a zipper-like structure in <b>X</b><sup><b>P</b></sup> is also in accordance with its existence in the aggregates of several
short amyloidogenic peptides. The computed values of translational
(<i>D</i><sub>T</sub>) and rotational (<i>D</i><sub>R</sub>) diffusion constants of 0.63 Ć 10<sup>ā6</sup> cm<sup>2</sup>/s and 0.035 ns<sup>ā1</sup>, respectively,
for this dimer are supported by the corresponding values of the AĪ²42
monomer. These simulations have also elucidated several other key
structural properties of these peptides. This information will be
very useful to design small molecules for the inhibition and disruption
of the critical AĪ²42 dimers