14 research outputs found
Realization of the structural fluctuation of biomolecules in solution: Generalized Langevin Mode Analysis
A new theoretical method, referred to as Generalized Langevin Mode Analysis
(GLMA), is proposed to analyze the mode of structural fluctuations of a
biomolecule in solution. The method combines the two theories in the
statistical mechanics, or the Generalized Langevin theory and the RISM/3D-RISM
theory, to calculate the second derivative, or the Hessian matrix, of the free
energy surface of a biomolecule in aqueous solution, which consists of the
intramolecular interaction among atoms in the biomolecule and the solvation
free energy. The method is applied to calculate the wave-number spectrum of an
alanine dipeptide in water for which the optical heterodyne-detected
Raman-induced spectroscopy (RIKES) spectrum is available to compare with. The
theoretical analysis reproduced the main features of the experimental spectrum
with respect to the peak positions of the four bands around ~90 cm-1, ~240
cm-1, ~370 cm-1, and 400 cm-1, observed in the experimental spectrum, in spite
that the physics involved in the two spectrum was not exactly the same: the
experimental spectrum includes the contributions from the dipeptide and the
water molecules interacting with the solute, while the theoretical one is just
concerned with the solute molecule, influenced by solvation. Two major
discrepancies between the theoretical and experimental spectra, one in the band
intensity around ~100 cm-1, and the other in the peak positions around ~370
cm-1, are discussed in terms of the fluctuation mode of water molecules
interacting with the dipeptide, which is not taken explicitly into account in
the theoretical analysis
Molecular Recognition and Self-Organization in Life Phenomena Studied by a Statistical Mechanics of Molecular Liquids, the RISM/3D-RISM Theory
There are two molecular processes that are essential for living bodies to maintain their life: the molecular recognition, and the self-organization or self-assembly. Binding of a substrate by an enzyme is an example of the molecular recognition, while the protein folding is a good example of the self-organization process. The two processes are further governed by the other two physicochemical processes: solvation and the structural fluctuation. In the present article, the studies concerning the two molecular processes carried out by Hirata and his coworkers, based on the statistical mechanics of molecular liquids or the RISM/3D-RISM theory, are reviewed
Predicting the Binding Mode of 2‑Hydroxypropyl-β-cyclodextrin to Cholesterol by Means of the MD Simulation and the 3D-RISM-KH Theory
It
has been found that a cyclodextrin derivative, 2-hydroxypropyl-β-cyclodextrin
(HPβCD), has reasonable therapeutic effect on Niemann-Pick disease
type C, which is caused by abnormal accumulation of unesterified cholesterol
and glycolipids in the lysosomes and shortage of esterified cholesterol
in other cellular compartments. We study the binding affinity and
mode of HPβCD with cholesterol to elucidate the possible mechanism
of HPβCD for removing cholesterol from the lysosomes. The dominant
binding mode of HPβCD with cholesterol is found based on the
molecular dynamics simulation and a statistical mechanics theory of
liquids, or the three-dimensional reference interaction site model
theory with Kovalenko-Hirata closure relation. We examine the two
types of complexes between HPβCD and cholesterol, namely, one-to-one
(1:1) and two-to-one (2:1). It is predicted that the 1:1 complex makes
two or three types of stable binding mode in solution, in which the
βCD ring tends to be located at the edge of the steroid skeleton.
For the 2:1 complex, there are four different types of the complex
conceivable, depending on the orientation between the two HPβCDs:
head-to-head (HH), head-to-tail (HT), tail-to-head (TH), and tail-to-tail
(TT). The HT and HH cyclodextrin dimers show higher affinity to cholesterol
compared to the other dimers and to all the binding modes of 1:1 complexes.
The physical reason why the HT and HH dimers have higher affinity
compared to the other complexes is discussed based on the consistency
with the 1:1 complex. On the one hand, in case of the HT and HH dimers,
the position of each CD in the dimer along the cholesterol chain comes
right on or close to one of the positions where a single CD makes
a stable complex. On the other hand, one of the CD molecules is located
on unstable region along the cholesterol chain, for the case of TH
and TT dimers
Predicting the Binding Mode of 2‑Hydroxypropyl-β-cyclodextrin to Cholesterol by Means of the MD Simulation and the 3D-RISM-KH Theory
It
has been found that a cyclodextrin derivative, 2-hydroxypropyl-β-cyclodextrin
(HPβCD), has reasonable therapeutic effect on Niemann-Pick disease
type C, which is caused by abnormal accumulation of unesterified cholesterol
and glycolipids in the lysosomes and shortage of esterified cholesterol
in other cellular compartments. We study the binding affinity and
mode of HPβCD with cholesterol to elucidate the possible mechanism
of HPβCD for removing cholesterol from the lysosomes. The dominant
binding mode of HPβCD with cholesterol is found based on the
molecular dynamics simulation and a statistical mechanics theory of
liquids, or the three-dimensional reference interaction site model
theory with Kovalenko-Hirata closure relation. We examine the two
types of complexes between HPβCD and cholesterol, namely, one-to-one
(1:1) and two-to-one (2:1). It is predicted that the 1:1 complex makes
two or three types of stable binding mode in solution, in which the
βCD ring tends to be located at the edge of the steroid skeleton.
For the 2:1 complex, there are four different types of the complex
conceivable, depending on the orientation between the two HPβCDs:
head-to-head (HH), head-to-tail (HT), tail-to-head (TH), and tail-to-tail
(TT). The HT and HH cyclodextrin dimers show higher affinity to cholesterol
compared to the other dimers and to all the binding modes of 1:1 complexes.
The physical reason why the HT and HH dimers have higher affinity
compared to the other complexes is discussed based on the consistency
with the 1:1 complex. On the one hand, in case of the HT and HH dimers,
the position of each CD in the dimer along the cholesterol chain comes
right on or close to one of the positions where a single CD makes
a stable complex. On the other hand, one of the CD molecules is located
on unstable region along the cholesterol chain, for the case of TH
and TT dimers
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Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides.
Naturally occurring peptides with high membrane permeability often have ester bonds on their backbones. However, the impact of amide-to-ester substitutions on the membrane permeability of peptides has not been directly evaluated. Here we report the effect of amide-to-ester substitutions on the membrane permeability and conformational ensemble of cyclic peptides related to membrane permeation. Amide-to-ester substitutions are shown to improve the membrane permeability of dipeptides and a model cyclic hexapeptide. NMR-based conformational analysis and enhanced sampling molecular dynamics simulations suggest that the conformational transition of the cyclic hexapeptide upon membrane permeation is differently influenced by an amide-to-ester substitution and an amide N-methylation. The effect of amide-to-ester substitution on membrane permeability of other cyclic hexapeptides, cyclic octapeptides, and a cyclic nonapeptide is also investigated to examine the scope of the substitution. Appropriate utilization of amide-to-ester substitution based on our results will facilitate the development of membrane-permeable peptides