Division of Chemical Sciences
https://etd.iisc.ac.in/handle/2005/10
2024-03-28T16:21:21Z2,3-Dideoxy Sugars in Glycoconjugations and Cyclic Oligosaccharide Synthesis
https://etd.iisc.ac.in/handle/2005/5957
2,3-Dideoxy Sugars in Glycoconjugations and Cyclic Oligosaccharide Synthesis
Sarkar, Biswajit
2,3- Dideoxy sugars are versatile synthons for organic synthesis. The
applications are diverse in biological systems and organic synthesis. In the first part of the
thesis, 2,3-unsaturated sugars are used for the glycoconjugation of amino acids, peptides and
proteins. In the later part, 2,3-dideoxy sugar is used to synthesize carbohydrate
macrocycle. Finally, sugar vinyl sulfoxide is used to synthesize substituted pyran via 2,6-
anhydro sugar formation.
Chapter 1 of the thesis is divided into two parts. The first part describes the literature
on unsaturated sugar, especially 2,3-unsaturated sugars, synthesis and their
modifications. Attention is given to their addition reactions with nucleophiles and
conjugation with biomolecules. A brief introduction to glycoconjugation is also reported in
this part. Different glycoconjugation methods are discussed briefly, and the advantages are
compared accordingly. The second part of this chapter elaborates on the synthesis of cyclic
oligosaccharides. The approaches and the difficulties in the respective
approaches are mentioned accordingly. Challenges with synthesising small cyclic
oligosaccharides are cited according to the available literature. Current development
in the field is also covered in the discussion.
Chapter 2 of the thesis deals with the glycoconjugation methods using sugar vinyl
sulfoxide involving Michael addition reaction. Glycoconjugations of amino acids, peptides
and protein, namely lysozyme are demonstrated in benign physiological conditions. The
smaller glycoconjugated molecules are characterized with the help of NMR spectroscopy
and mass spectrometry, while the larger glycoconjugated peptide and protein are
characterized with the help of mass spectrometry. Biophysical studies of glycoconjugated
lysozyme showed increased stability in the presence of trypsin while retaining its antimicrobial
activity. Thus, a benign glycoconjugation method is developed.
Chapter 3 of the thesis unravels further potential of glycoconjugation using sugar vinyl
sulfoxide. PETIM dendrimers of generation zero to three are glycoconjugated with sugar
vinyl sulfoxide. The glycoconjugations of the lower generation dendrimers are confirmed
using NMR spectroscopy and mass spectrometry; for higher generations, only NMR
spectroscopy was employed for the characterization. The first-order reaction rate constant
of the glycoconjugation reaction is also determined using NMR spectroscopy. Further
biological evaluation of the native and glycoconjugated PETIM dendrimer reveals that
PETIM dendrimers show selective antibacterial activity against M. smegmatis, and the
native dendrimers show higher efficacy over the glycoconjugated dendrimer.
Chapter 4 of the thesis describes the synthesis of the cyclic disaccharide molecule
composed of 2,3-dideoxy furanoside monomer units. The synthesis started from protected
glucal molecules and followed a few simple reaction steps, including the Ferrier reaction,
desulfurization reaction, and selective hydroxy group protection and finally,
glycoconjugation reaction. While the formation of the disaccharide is confirmed using NMR
spectroscopy and mass spectrometry, the conformation of the constituting monomeric unit
of the cyclic disaccharide is ascertained through solid state structure determination using
the single crystal X-ray diffraction method. The ring contraction of the pyranoside monomer to
furanoside cyclic disaccharide is explained by two plausible mechanisms involved in the
glycosylation step. Further encapsulation property of the cyclic disaccharide molecule was
evaluated against the 1-aminoadamantane using the ITC method. This experiment allows looking into the thermodynamics of the encapsulation and the encapsulation mode of the
molecule.
Chapter 5 of the thesis shows sugar vinyl sulfoxide's application and potential
as a synthetic intermediate. Intra-molecular Michael addition reaction of the sugar vinyl
sulfoxide in basic condition affords elusive 2,6-anhydro sugar molecules in a single step.
Selective opening of the bicyclic ring of the anhydro sugar converts it to a substituted
pyran. The applicability of this two-step, one-pot reaction is also tested on sugar vinyl
sulfoxide derived from galactal.
The thesis describes the achievement of the diversification of 2,3-unsaturated sugar. A
benign glycoconjugation method is developed and adequately characterized. The synthetic
potential of 2,3-dideoxy sugar is demonstrated through the synthesis of cyclic disaccharide
via a ring contraction of pyranoside to a furanoside. And finally, a two-step reaction
protocol converts pyranoside sugar into a substituted pyran.
Ab Initio Molecular Dynamics Studies of Bronsted Acid-Base Chemistry in Aqueous Solutions
https://etd.iisc.ac.in/handle/2005/3943
Ab Initio Molecular Dynamics Studies of Bronsted Acid-Base Chemistry in Aqueous Solutions
Tummanapelli, Anil Kumar
Knowledge of the dissociation constants of the ionizable protons of weak acids in aqueous media is of fundamental importance in many areas of chemistry and biochemistry. The pKa value, or equilibrium dissociation constant, of a molecule determines the relative concentration of its protonated and deprotonated forms at a specified pH and is therefore an important descriptor of its chemical reactivity. Considerable efforts have been devoted to the determination of pKa values by deferent experimental techniques. Although in most cases the determination of pKa values from experimental is straightforward, there are situations where interpretation is difficult and the results ambiguous. It is, therefore, not surprising that the capability to provide accurate estimates of the pKa value has been a central goal in theoretical chemistry and there has been a large effort in developing methodologies for predicting pKa values for a variety of chemical systems by differing quantum chemical techniques. A prediction accuracy within 0.5 pKa units of experiment is the desirable level of accuracy. This is a non-trivial exercise, for an error of 1 kcal/mol in estimates of the free energy value would result in an error of 0.74 pKa units.
In this thesis ab initio Car-Parrinello molecular dynamics (CPMD) has been used for investigating the Brϕnsted acid-base chemistry of weak acids in aqueous solution. A key issue in any dissociation event is how the solvating water molecules arrange themselves spatially and dynamically around the neutral and dissociated acid molecule. Ab initio methods have the advantage that all solvent water molecules can, in principle, be con- sidered explicitly. One of the factors that has inhibited the widespread use of ab initio MD methods to study the dissociation reaction is that dissociation of weak acids are rare events that require extremely long simulation times before one is observed. The metady- namics formalism provides a solution to this conundrum by preventing the system from revisiting regions of configuration space where it has been in the past. The formalism allows the system to escape the free-energy minima by biasing the dynamics with a history dependent potential (or force) that acts on select degrees of freedom, referred to as collective variables. The bias potentials, modeled by repulsive inverted Gaussians that are dropped during propagation, drive the system out of any free-energy minima and allow it to explore the configuration space by a relatively quick and efficient sampling. The the- sis deals with a detailed investigation of the Brϕnsted acid-base chemistry of weak acids in aqueous solutions by the CPMD-metadynamics procedure.
In Chapter 1, current approaches for the theoretical estimation of pKa values are summarized while in Chapter 2 the simulation methodology and the metadynamics sampling techniques used in thisstudy are described.
The potential of the CPMD-metadynamics procedure to provide estimates of the acid dissociation constant (pKa) is explored in Chapter 3, using acetic acid as a test sys- tem. Using the bond-distance dependent coordination number of protons bound to the dissociating carboxylic groups as the collective variable, the free-energy profile for the dissociation reaction of acetic acid in water was computed. Convergence of the free-energy profiles and barriers for the simulations parameters is demonstrated. The free-energy profiles exhibit two distinct minima corresponding to the dissociated and neutral states of the acid and the deference in their values provides the estimate for pKa. The estimated value of pKa for acetic acid from the simulations, 4.80, is in good agreement with the experiment at value of 4.76. It is shown that the good agreement with experiment is a consequence of the cancellation of errors, as the pKa values are computed as the difference in the free energy values at the minima corresponding to the neutral and dissociated state. The chapter further explores the critical factors required for obtaining accurate estimates of the pKa values by the CPMD-metadynamics procedure. It is shown that having water molecules sufficient to complete three hydration shells as well as maintaining water density in the simulation cell as close to unity is important.
In Chapter 4, the CPMD-metadynamics procedure described in Chapter-3 has been used to investigate the dissociation of a series of weak organic acids in aqueous solutions. The acids studied were chosen to highlight some of the major factors that influence the dissociation constant. These include the influence of the inductive effect, the stabilization of the dissociated anion by H-bonding as well as the presence of multiple ionizable groups. The acids investigated were aliphatic carboxylic acids, chlorine-substituted carboxylic acids, cid and trans-butenedioic, the isomers of hydroxybenzoic acid and phthalic acids and its isomers. It was found that in each of these examples the CPMD-metadynamics procedure correctly estimates the pKa values, indicating that the formulism is capable of capturing these influences and equally importantly indicating that the cancellation of errors is indeed universal. Further, it is shown that the procedure can provide accurate estimates of the successive pKa values of polypro tic acids as well as the subtle deference in their values for deterrent isomers of the acid molecule.
Changes in protonation-deprotonation of amino acid residues in proteins play a key role in many biological processes and pathways. It is shown that CPMD simulations in conjunction with metadynamics calculations of the free energy profile of the protonation- deprotonation reaction can provide estimates of the multiple pKa values of the 20 canonical α-amino acids in aqueous solutions in good agreement with experiment (Chapter 5). The distance-dependent coordination number of the protons bound to the hydroxyl oxygen of the carboxylic and the amine groups is used as the collective variable to explore the free energy profiles of the Brϕnsted acid-base chemistry of amino acids in aqueous solutions. Water molecules, sufficient to complete three hydration shells surrounding the acid molecule were included explicitly in the computation procedure. The method works equally well for amino acids with neutral, acidic and basic side chains and provides estimates of the multiple pKa values with a mean relative error with respect to experimental results, of 0.2 pKa units.
The tripeptide Glutathione (GSH) is one of the most abundant peptides and the major repository for non-protein sulfur in both animal and plant cells. It plays a critical role in intracellular oxidative stress management by the reversible formation of glutathione disulfide with the thioldisulfide pair acting as a redox buffer. The state of charge of the ionizable groups of GSH can influences the redox couple and hence the pKa value of the cysteine residue of GSH is critical to its functioning. In Chapter 6, it has been reported that ab initio Car-Parrinello Molecular Dynamics simulations of glutathione solvated by 200 water molecules, all of which are considered in the simulation. It is shown that the free-energy landscape for the protonation - deprotonation reaction of the cysteine residue of GSH computed using metadynamics sampling provides accurate estimates of the pKa and correctly predicts the shift in the dissociation constant values as compared to the isolated cysteine amino acid.
The dissociation constants of weak acids are commonly determined from pH-titration
curves. For simple acids the determination of the pKa from the titration curves using the Henderson-Hasselbalch equation is relatively straightforward. There are situations, however, especially in polypro tic acids with closely spaced dissociation constants, where titration curves do not exhibit clear inflexion and equivalence stages and consequently the estimation of multiple pKa values from a single titration curve is no longer straightfor-
ward resulting in uncertainties in the determined pKa values. In Chapter 7, the multiple
dissociation constant of the hexapeptide glutathione disulfide (GSSG) with six ionizable groups and six associated dissociation constants has been investigated. The six pKa values of GSSG were estimated using the CPMD-metadynamics procedure from the free-energy profiles for each dissociation reaction computed using the appropriate collective variable. The six pKa values of GSSG were estimated and the theoretical pH-titration curve was then compared with the experimentally measured pH-titration curve and found to be in excellent agreement. The object of the exercise was to establish whether interpretation of pH-titration curves of complex molecules with multiple ionizable groups could be facilitated using results of ab initio molecular dynamics simulations.
2018-08-11T00:00:00ZAb-initio Modeling and Designing of Materials for Thermoelectrics, Optoelectronics and High Temperature Applications
https://etd.iisc.ac.in/handle/2005/4896
Ab-initio Modeling and Designing of Materials for Thermoelectrics, Optoelectronics and High Temperature Applications
Samanta, Atanu
Designing a material for a particular application requires an atomistic understanding of its
properties. Recent development in first principles methods and supercomputing speeds has
enabled researchers to compute materials properties accurately. This has opened up a window
for computational designing of materials for various applications such as optoelectronics,
thermoelectrics, magnetic shape memory alloys etc. In this thesis, first principles methods
have been utilized to understand the properties of various materials such as TiS2, TiS3, GeO2,
Co3(MoTaAl) alloys, Ni2MnGa and graphene. This thesis has been organized as follows:
• Chapter 1 introduces various functional materials and their application in the thermoelectric,
optoelectronic, high temperature and magnetic shape memory. The microscopic
understanding of materials properties such as structure, energetics, electronic structure,
electronic transport, and lattice dynamics etc. can lead to novel ways of designing materials
properties for various applications.
• Chapter 2 describes the theoretical methodology adopted in this work. It gives a brief
understanding of first principles based density functional theory (DFT) and various approximations
to obtain accurate electronic properties. Methods employed for calculation
of electronic and thermal transport are also discussed briefly.
• In Chapter 3 we explore the tuning of the electronic structure of the transition metal
dichalogenide TiS2. We show that by engineering its electronic structure, it transforms
from a semimetal to a semiconductor under biaxial strain. The thermoelectrics study
shows that a 3 fold enhancement in thermopower can be achieved by application of 5%
biaxial strain. This enhancement is driven by a small bandgap opening of ∼0.15 eV, which
increases its thermopower at the same time decreasing its lattice thermal conductivity
indicating improvement in ZT.
• In Chapter 4 we study the possibility of inherent stacking fault in bulk TiS3 and its effect
on the electronic properties. We find that TiS3 can exist in AB′ and AB′′ geometries. The
energy difference between two structures is about 0.011 eV/f.u. The electronic structure
is independent of the stacking fault due to the weak vdW interaction between the layers.
The calculated thermopower is 200 μV/K in the carrier concentration range of 1×1020
cm−3 - 5×1020 cm−3, which is comparable with other state of the art thermoelectric
materials. The high thermopower and electrical conductivity in the carrier concentration
range of 1×1020 cm−3 - 5×1020 cm−3 leads to a high power factor for both p- and n-type.
Moreover, the power factor for p-type is three times higher than that of n-type carriers
indicating that the thermoelectric performance for p-type will be much better than that
of n-type.
• Chapter 5 reveals the origin behind the large variation in the band gap (∼ 2 eV) of
GeO2 calculated by standard DFT within LDA/GGA, which had remained unresolved.
Using the many-body perturbation theory (GW approximation), we find that this large
variation observed in literature is independent of the method used and depends strongly
on the lattice parameter (volume strain). This strong dependence originates from a change
in hybridization among O-p and Ge-(s and p) orbitals.
• Chapter 6 deals with the structural stability of order intermetallic Co-based superalloys.
We have shown that W free Co3Al order structure can be stabilized in L12 structure by
addition of Mo and Ta atoms. The enthalpy of formation of L12 structure significantly
becomes more negative compared to the DO19 structure by the addition of ≥ 4% of Ta
atoms. This implies that the L12 structure of Co3(Al,Mo,Ta) structure is more stable
compared to DO19. The lowering in the enthalpy of formation is found due to the formation
of the pseudo gap and the decrease in the states at the pseudo gap with increasing Ta
concentration. The stability of the L12 structure can be further improved by the addition
of Ni and Ti atoms.
• In Chapter 7, the lattice dynamics and electronic structure of X2YZ [where X = Ni,
Fe, Co; Y = Mn; Z = Al, Ga, Ge, In, Sn, Sb] stoichiometry compounds are investigated.
The lattice instability of X2MnZ depends on the position of the Fermi energy (EF ) with
respect to the pseudo gap. The phonon mode softening along the Γ-K symmetry direction
is observed for Ni2MnZ in the austenite phase since EF is located above the pseudo gap.
This mode softening is mainly responsible for the MSM effect. On the other hand, Fe2MnZ
and Co2MnZ [Z = Al, Ga, Ge, In, Sn, Sb] in the cubic phase do not show any phonon
mode softening because EF lies in the vicinity of the pseudo gap or at the pseudo gap.
Thus, alloying Fe or Co at the Ni site in Ni2Mn (Z = groups-IV and V) can tune the lattice
modulation. In addition, the magnetic moments of Fe2Mn (Z = groups-IV and V) and
Co2Mn (Z = groups-IV and V) are much higher than those of Ni2Mn (Z = groups-IV and
V), indicating that the magnetic moments of Ni2MnZ can be enhanced. The calculated
phonon dispersion with magnetic moment indicates that the phonon mode softening is
sensitive to the change in the local magnetic moment of the atoms, thereby enabling
tunability in the MSM effect.
• In chapter 8, we show that the mono vacancy defects in graphene can be used as precursors
to form novel clipped structures without explicit use of functional groups. These
clipped structures can be transformed into one-dimensional (1D) double wall nanotubes
(DWCNT) or multi-layered three dimensional (3D) structures. The clipped structures
show good mechanical strength due to covalent bonding between multi-layers. Clipping
also provides a unique way to simultaneously harness the conductivity of both walls of
a double wall nanotube through covalently bonded scattering junctions. With additional
conducting channels and improved mechanical stability, these clipped structures can lead
to a myriad of applications in novel devices.
• Chapter 9 summarizes and concludes the work presented in this thesis.
Accelerated search for thermoelectric and topological materials using first-principles and machine learning
https://etd.iisc.ac.in/handle/2005/4699
Accelerated search for thermoelectric and topological materials using first-principles and machine learning
Juneja, Rinkle
In summary, we have performed first-principles calculations to study the topological phase transitions
in chalcopyrite compounds as a function of hydrostatic pressure. These compounds are
topological insulators in the native phase with an inverted band order around BZ center. Upon
hydrostatic compression, there is a transition from nontrivial TI phase to a Dirac semimetallic
state at a critical pressure. Further increase in pressure drives the materials into a trivial semiconductors
along with normal ordering of bands. Different quantum phases are characterized
by topological invariants as well as surface states. These quantum phase transitions are further
validated by model calculations based on L¨uttinger Hamiltonian, which unravels the critical
role played by pressure-induced anisotropy of frontier bands in driving the phase transitions.
Such a manoeuvre between various topological phases by hydrostatic pressure can stimulate
the search for TQPTs in future experiments