24 research outputs found
Dynamical coupling between protein conformational fluctuation and hydration water: Heterogeneous dynamics of biological water
We investigate dynamical coupling between water and amino acid side-chain
residues in solvation dynamics by selecting residues often used as natural
probes, namely tryptophan, tyrosine and histidine, located at different
positions on protein surface and having various degrees of solvent exposure.
Such differently placed residues are found to exhibit different timescales of
relaxation. The total solvation response, as measured by the probe is
decomposed in terms of its interactions with (i) protein core, (ii) side-chain
atoms and (iii) water molecules. Significant anti cross-correlations among
these contributions are observed as a result of side-chain assisted energy flow
between protein core and hydration layer, which is important for the proper
functionality of a protein. It is also observed that there are rotationally
faster as well as slower water molecules than that of bulk solvent, which are
considered to be responsible for the multitude of timescales that are observed
in solvation dynamics. We also establish that slow solvation derives a
significant contribution from protein side-chain fluctuations. When the motion
of the protein side-chains is forcefully quenched, solvation either becomes
faster or slower depending on the location of the probe.Comment: 12 pages and 6 figures(coloured
On the origin of diverse time scales in the protein hydration layer solvation dynamics: A molecular dynamics simulation study
In order to inquire the microscopic origin of observed multiple time scales
in solvation dynamics we carry out several computer experiments. We perform
atomistic molecular dynamics simulations on three protein-water systems namely,
Lysozyme, Myoglobin and sweet protein Monellin. In these experiments we mutate
the charges of the neighbouring amino acid side chains of certain natural
probes (Tryptophan) and also freeze the side chain motions. In order to
distinguish between different contributions, we decompose the total solvation
energy response in terms of various components present in the system. This
allows us to capture the interplay among different self and cross-energy
correlation terms. Freezing the protein motions removes the slowest component
that results from side chain fluctuations, but a part of slowness remains. This
leads to the conclusion that the slow component in the ~20-80 ps range arises
from slow water molecules present in the hydration layer. While the more than
100 ps component may arise from various sources namely, adjacent charges in
amino acid side chains, the water molecules that are hydrogen bonded to them
and a dynamically coupled motion between side chain and water. The charges, in
addition, enforce a structural ordering of nearby water molecules and helps to
form local long-lived hydrogen bonded network. Further separation of the
spatial and temporal responses in solvation dynamics reveals different roles of
hydration and bulk water. We find that the hydration layer water molecules are
largely responsible for the slow component whereas the initial ultrafast decay
arise predominantly (~80%) due to the bulk. This agrees with earlier
theoretical observations. We also attempt to rationalise our results with the
help of a molecular hydrodynamic theory that was developed using classical time
dependent density functional theory in a semi quantitative manner.Comment: 27 pages, 9 figure
Towards Understanding the Structure, Dynamics and Bio-activity of Diabetic Drug Metformin
Small molecules are often found to exhibit extraordinarily diverse biological
activities. Metformin is one of them. It is widely used as anti-diabetic drug
for type-two diabetes. In addition to that, metformin hydrochloride shows
anti-tumour activities and increases the survival rate of patients suffering
from certain types of cancer namely colorectal, breast, pancreas and prostate
cancer. However, theoretical studies of structure and dynamics of metformin
have not yet been fully explored. In this work, we investigate the
characteristic structural and dynamical features of three mono-protonated forms
of metformin hydrochloride with the help of experiments, quantum chemical
calculations and atomistic molecular dynamics simulations. We validate our
force field by comparing simulation results to that of the experimental
findings. Nevertheless, we discover that the non-planar tautomeric form is the
most stable. Metformin forms strong hydrogen bonds with surrounding water
molecules and its solvation dynamics show unique features. Because of an
extended positive charge distribution, metformin possesses features of being a
permanent cationic partner toward several targets. We study its interaction and
binding ability with DNA using UV spectroscopy, circular dichroism, fluorimetry
and metadynamics simulation. We find a non-intercalating mode of interaction.
Metformin feasibly forms a minor/major groove-bound state within a few tens of
nanoseconds, preferably with AT rich domains. A significant decrease in the
free-energy of binding is observed when it binds to a minor groove of DNA.Comment: 60 pages, 24 figure
Thermodynamic forces from protein and water govern condensate formation of an intrinsically disordered protein domain
Abstract Liquid-liquid phase separation (LLPS) can drive a multitude of cellular processes by compartmentalizing biological cells via the formation of dense liquid biomolecular condensates, which can function as membraneless organelles. Despite its importance, the molecular-level understanding of the underlying thermodynamics of this process remains incomplete. In this study, we use atomistic molecular dynamics simulations of the low complexity domain (LCD) of human fused in sarcoma (FUS) protein to investigate the contributions of water and protein molecules to the free energy changes that govern LLPS. Both protein and water components are found to have comparably sizeable thermodynamic contributions to the formation of FUS condensates. Moreover, we quantify the counteracting effects of water molecules that are released into the bulk upon condensate formation and the waters retained within the protein droplets. Among the various factors considered, solvation entropy and protein interaction enthalpy are identified as the most important contributions, while solvation enthalpy and protein entropy changes are smaller. These results provide detailed molecular insights on the intricate thermodynamic interplay between protein- and solvation-related forces underlying the formation of biomolecular condensates