jp8b02098_si_002.zip (4.75 MB)
Predicting the Binding Mode of 2‑Hydroxypropyl-β-cyclodextrin to Cholesterol by Means of the MD Simulation and the 3D-RISM-KH Theory
dataset
posted on 2018-03-13, 00:00 authored by Yuji Hayashino, Masatake Sugita, Hidetoshi Arima, Tetsumi Irie, Takeshi Kikuchi, Fumio HirataIt
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.