Sajeev Chacko

Why Do Gallium Clusters Have a Higher Melting Point than the Bulk

Density functional molecular dynamical simulations have been performed on Ga17 and Ga13 clusters to understand the recently observed higher-than-bulk melting temperatures in small gallium clusters [Phys. Rev. Lett. 91, 215508 (2003)]]. The specific-heat curve, calculated with the multiple-histogram technique, shows the melting temperature to be well above the bulk melting point of 303 K, viz., around 650 and 1400 K for Ga17 and Ga13, respectively. The higher-than-bulk melting temperatures are attributed mainly to the covalent bonding in these clusters, in contrast with the covalent-metallic bonding in the bulk.

Ferromagnetism in Carbon-Doped Zinc Oxide Systems

We report spin-polarized density functional calculations of ferromagnetic properties for a series of ZnO clusters and ZnO solid containing one or two substitutional carbon impurities. We analyze the eigenvalue spectra, spin densities, molecular orbitals, and induced magnetic moments for ZnC, Zn(2)C, Zn(2)OC, carbon-substituted Zn(n)O(n) (n = 3-10, 12) clusters and the bulk ZnO. The results show that the doping induces magnetic moment of approximately 2 mu(B) in all the cases. All systems with two carbon impurities show ferromagnetic interaction, except when carbon atoms share the same zinc atom as the nearest neighbor. This ferromagnetic interaction is predominantly mediated via pi-bonds in the ring structures and through pi- and sigma-bonds in the three-dimensional structure. The calculations also show that the interaction is significantly enhanced in the solid, bringing out the role of dimensionality of the Zn-O network connecting two carbon atoms.

First-principles investigation of finite-temperature behavior in small sodium clusters.

A systematic and detailed investigation of the finite-temperature behavior of small sodium clusters, Na(n), in the size range of n=8-50 are carried out. The simulations are performed using density-functional molecular dynamics with ultrasoft pseudopotentials. A number of thermodynamic indicators such as specific heat, caloric curve, root-mean-square bond-length fluctuation, deviation energy, etc., are calculated for each of the clusters. Size dependence of these indicators reveals several interesting features. The smallest clusters with n=8 and 10 do not show any signature of melting transition. With the increase in size, broad peak in the specific heat is developed, which alternately for larger clusters evolves into a sharper one, indicating a solidlike to liquidlike transition. The melting temperatures show an irregular pattern similar to the experimentally observed one for larger clusters [Schmidt et al., Nature (London) 393, 238 (1998)]. The present calculations also reveal a remarkable size-sensitive effect in the size range of n=40-55. While Na(40) and Na(55) show well-developed peaks in the specific-heat curve, Na(50) cluster exhibits a rather broad peak, indicating a poorly defined melting transition. Such a feature has been experimentally observed for gallium and aluminum clusters [Breaux et al., J. Am. Chem. Soc. 126, 8628 (2004); Breaux et al., Phys. Rev. Lett. 94, 173401 (2005)].

Novel Natural Structure Corrector of ApoE4 for Checking Alzheimer’s Disease: Benefits from High Throughput Screening and Molecular Dynamics Simulations

A major genetic suspect for Alzheimers disease is the pathological conformation assumed by apolipoprotein E4 (ApoE4) through intramolecular interaction. In the present study, a large library of natural compounds was screened against ApoE4 to identify novel therapeutic molecules that can prevent ApoE4 from being converted to its pathological conformation. We report two such natural compounds PHC and IAH that bound to the active site of ApoE4 during the docking process. The binding analysis suggested that they have a strong mechanistic ability to correct the pathological structural orientation of ApoE4 by preventing repulsion between Arg 61 and Arg 112, thus inhibiting the formation of a salt bridge between Arg 61 and Glu 255. However, when the molecular dynamics simulations were carried out, structural changes in the PHC-bound complex forced PHC to move out of the cavity thus destabilizing the complex. However, IAH was structurally stable inside the binding pocket throughout the simulations trajectory. Our simulations results indicate that the initial receptor-ligand interaction observed after docking could be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favored and should be better representations of derivative poses in the receptor.

Targeting the intersubunit cavity of Plasmodium falciparum glutathione reductase by a novel natural inhibitor: computational and experimental evidence.

Glutathione reductase (GR), a homodimeric FAD-dependent disulfide reductase, is essential for redox homeostasis of the malaria parasite Plasmodium falciparum and has been proposed as an antimalarial drug target. In this study we performed a virtual screening against PfGR, using the structures of about 170,000 natural compounds. Analysis of the two top-scoring molecules, TTB and EPB, indicated that these ligands are likely to interact with the homodimer intersubunit cavity of PfGR with high binding energy scores of -9.67 and -9.60kcal/mol, respectively. Both compounds had a lower affinity for human GR due to differences in structure and electrostatic properties. In order to assess the putative interactions in motion, molecular dynamics simulations were carried out for 30ns, resulting in TTB being more dynamically and structurally favored than EPB. A closely related compound MDPI 21618 was tested on recombinant PfGR and hGR, resulting in IC50 values of 11.3±2.5μM and 10.2±1.7μM, respectively. Kinetic characterization of MDPI 21618 on PfGR revealed a mixed-type inhibition with respect to glutathione disulfide (Ki=9.7±2.3μM) and an uncompetitive inhibition with respect to NADPH. Furthermore, MDPI 21618 was found to inhibit the growth of the chloroquine-sensitive P. falciparum strain 3D7 with an IC50 of 3.2±1.9μM and the chloroquine-resistant Dd2 strain with an IC50 of 3.2+1.6μM. In drug combination assays with chloroquine, artemisinin, or mefloquine MDPI 21618 showed an antagonistic action, which might suggest partially overlapping routes of action. This study further substantiates research on PfGR as a potential antimalarial drug target.

Resisting resistant Mycobacterium tuberculosis naturally: Mechanistic insights into the inhibition of the parasite’s sole signal peptidase Leader peptidase B

Tuberculosis (TB) is the second highest cause of mortality after HIV/AIDS and is one of the leading public health problems worldwide. The growing resistance to anti-TB drugs and the recalcitrant nature of tenacious infections present arduous challenges for the treatment of TB. Thus, the need to develop therapeutics against novel drug targets to help overcome multi-drug resistant TB is inevitable. Leader peptidase B (LepB), the sole signal peptidase of Mycobacterium tuberculosis (MTb), is one such potential drug target. The present work aims at identifying potential inhibitors of LepB, so as to repress the formation of the functional proteins essential for the growth and pathogenesis of MTb. In this study, we screened a large dataset of natural compounds against LepB using a high throughput approach. The screening was directed toward a binding pocket consisting of residues, some of which are critical for the catalytic activity of the enzyme, while others are part of the conserved domains of the signal peptidases. We also carried out molecular dynamics simulations of the two top-scoring compounds in order to study their molecular interactions with the active site functional residues of LepB and also to assess their dynamic behavior. We report herein two prospective non-covalent type inhibitory drugs of natural origin which are active against tuberculosis. These lead molecules possess improved binding properties, have low toxicity and are specific against MTb.

Hydrogen adsorption on Na–SWCNT systems

We investigate the hydrogen adsorption capacity of Na-coated carbon nanotubes (Na-SWCNTs) using first-principles electronic structure calculations at absolute temperature and pressure. A single Na atom is always found to occupy the hollow site of a hexagonal carbon ring in all the six different SWCNTs considered, with a nearly uniform Na–C bond length of 2.5 A. Semiconducting zigzag nanotubes, (8,0) and (5,0), show stronger binding energies for the Na atom (−2.1 eV and −2.6 eV respectively), as compared to metallic SWCNTs with armchair and chiral geometries. The single Na atom can further adsorb up to six hydrogen molecules with a relatively constant binding energy of −0.26 eV per H2. Mulliken population analysis shows that positively charged Na atoms with 0.82e charge transfer to nearest carbon atoms which polarizes the SWCNT leading to local dipole moments. This charge-induced dipole interaction is responsible for the higher hydrogen uptake of Na-coated SWCNTs. The transition state search shows that the diffusion barrier of Na atom on the SWCNT between two adjoining C–C rings is 0.35 eV. We also investigate the clustering of Na atoms to find out the maximum weight percentage adsorption of H2 molecules. At high Na coverage, we show that Na-coated SWCNTs can adsorb 9.2–11.28 wt% hydrogen. Our analysis shows that, although indeed Na-coated SWCNTs present potential materials for the hydrogen storage, care should be taken to avoid Na atoms clustering on the support material at elevated temperature and pressure, to achieve higher hydrogen capacity.