Dynamical Heterogeneity of Interface Water upon Membrane Phase Transitions
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Date
2023-01
Researcher
Malik, Sheeba
Supervisor
Debnath, Ananya
Journal Title
Journal ISSN
Volume Title
Publisher
Indian Institute of Technology Jodhpur
Abstract
Lipid bilayers are essential components of cell membranes because they serve as
semi-permeable barriers between the extracellular and intracellular environments. Fluid (Lα ),
ripple (Pβ ), and gel (Lβ ) are the three primary phases of lipid membranes. The functionality
of the cell membrane is active at its fluid phase and at a full hydration level. A co-existence
in the gel and the fluid phases in membranes results in the creation of grain boundary defects
and helps in a drug release. Water molecules near membranes regulate various properties of
the cell such as transport, raft formation, molecular recognition, signal transduction and so on.
Such water have different characteristics than bulk water (BW). Thus understanding the role of
water on the membrane phase transitions is crucial to control the function of membrane under
physiological and low temperature conditions. Although water dynamics and thermodynamics
around membranes have been found to be correlated with the phase transition, the underlying
mechanism of the correlation is not explored and not characterized. The current thesis provides
evidences of emergence of dynamical heterogeneity in interface water (IW) near membranes at
three phases using all-atom molecular dynamics simulations. The correlation between the structure
and dynamics of the IW and membranes are quantified across fluid to ripple to gel phase transitions. To understand whether the regional coupling of lipid and water dynamics is significant
enough to capture any perturbation in fluid membrane, we identify IW near a fluid membrane
composed of 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) lipids. IW residing within
a distance of ±0.35 nm of the locations of the most probable density of CO/PO/Glyc. heads of
DMPC molecules are referred to as IW-COd/POd/Glycd . All IW molecules manifest signatures of
dynamical heterogeneity at room temperature due to regional confinement and exhibit multiple
structural relaxation time-scales. Both fast and slow relaxation time scales of the IWd are
correlated to the respective time scales of the closest lipid moieties. These analyses imply that the
spatially resolved interface water dynamics can act as a sensitive reflector of regional membrane
dynamics occurring at sub ps to hundreds of ps time scales and thus will be able to capture
any alterations in membrane structure and function in future. Since membranes are active at a
fully hydrated state and the cells die upon dehydration, understanding biological cell membranes
under anhydrous conditions is of tremendous importance. We find that the bilayer undergoes
from a disordered state to a ordered state upon dehydration with a drastic slow-down in the
relaxation times of the IW originated from dynamical heterogeneity. The diffusion constants
and the structural relaxation times of the IW obey the Stokes-Einstein (SE) relation for the
bilayer fluid phase which changes to a fractional SE-like relation at the onset of bilayer ordering.
Thus, our analysis provides the mechanistic insights of dehydration induced bilayer ordering.
To understand the structural changes of the IW due to bilayer phase transitions, we perform a
∼ 11.55μs long all-atom molecular dynamics simulation at the gel, ripple and the fluid phases
of the bilayers. The first and second peak heights of the radial distribution functions (RDF)
of the BW increase monotonically with a decrease in temperature, signifying the presence of
enhanced tetrahedrality at the lowest temperature which is below the homogeneous ice nucleation
temperature accessing the ”no man’s land”. Similar behaviour is observed for the IW near fluid and
gel phases but not for the ripple phase, probably due to the curvature induced in the ripple phase.
Changes in locations of the first and the second hydration shells show two crossovers near fluid to
ripple and ripple to gel phase transitions. The angular distribution functions of the IW near the
fluid bilayers exhibit peaks corresponding to a distorted tetrahedral arrangement similar to the
high-density liquid (HDL) phase due to the presence of interstitials. This changes to tetrahedral arrangement for the IW near the gel bilayer, indicating the presence of low-density liquid (LDL)
like phases. As temperature reduces, membrane phase transitions are associated with a drastic
slow down in structural relaxation times of the interface water (IW) and the lipids originated
from dynamical heterogeneity. Diffusion constants of the IW undergo dynamic crossovers at both
fluid-to-ripple-to-gel phase transitions with the highest activation energy near the gel phase leading
to a stronger correlation of the IW dynamics with the gel membrane due to larger number of
hydrogen bonds. Similar to the BW, Stoke Einstein (SE) relations are conserved for the IW near
all three phases of membranes for the time scales derived from the diffusion exponents and the
non-Gaussian parameters, indicating that these time scales are coupled with the diffusion even at
lower temperatures. However, the SE relationship breaks for the time scales calculated from the
self intermediate scattering functions. The behavioural differences in these different time scales
upon supercooling are found to be universal irrespective of the nature of the water and other
glass forming liquids. The spatial correlation length scale of the heterogeneous local dynamics of
the IW are captured from the data collapse of block size dependent Binder cumulant which is
a scaling function of only the underlying correlation length. The dynamical length of the IW is
found to have inverse power law dependence on temperature for the fluid phase. The dependence
becomes very weak for the gel phase unlike glass forming liquids. Interestingly, the dynamical
length scale of the IW near the ripple phase is temperature independent and thus, can capture
to the domain size of the ripple signifying a possibility of probing the heterogeneity length scale
of a bio-membrane from its curvature induced domain size. The length scale is monotonically
dependent on the first peak of the radial distribution function of the IW near all phases this
suggests that the heterogeneity length scale is structure dominated. Our analyses, for the first
time, estimate the coupling between the spatio-temporal scales of the IW and membranes across
phase transitions. The structural relaxations of the IW follow an activated dynamical scaling with
the heterogeneity length scale only for the gel phase which is similar to that predicted from the
random first order transition theory. However, the drastic growths in the heterogeneity length
scale across phase transitions are not accompanied by similar growth in the heterogeneity time
scales. This is because, the growing structural relaxation time scales of the IW are dominated by
the supercooling whereas the growing length scales are dictated by the membrane phase transitions. In summary, the thesis sheds light on how the structure and dynamics of lipids and IW
are correlated across a wide range of temperature and hydration numbers relevant for physiological
and extreme conditions. Our findings suggest that hydration water dynamics can sensitively reflect
localized membrane movements and thus can be an alternate tool to probe any perturbations in
membranes. These can help to understand drug delivery mechanisms and mimic cryo preservation
procedures for use in biomedical applications in the future.
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Citation
Malik, Sheeba. (2023). Dynamical Heterogeneity of Interface Water upon Membrane Phase Transitions (Doctor's thesis). Indian Institute of Technology Jodhpur, Jodhpur.