Lalith Perera

A smooth particle mesh Ewald method

The previously developed particle mesh Ewald method is reformulated in terms of efficient B‐spline interpolation of the structure factors. This reformulation allows a natural extension of the method to potentials of the form 1/rp with p≥1. Furthermore, efficient calculation of the virial tensor follows. Use of B‐splines in place of Lagrange interpolation leads to analytic gradients as well as a significant improvement in the accuracy. We demonstrate that arbitrary accuracy can be achieved, independent of system size N, at a cost that scales as N log(N). For biomolecular systems with many thousands of atoms this method permits the use of Ewald summation at a computational cost comparable to that of a simple truncation method of 10 A or less.

New tricks for modelers from the crystallography toolkit: the particle mesh Ewald algorithm and its use in nucleic acid simulations

We thank the North Carolina Supercomputing Center, the Pittsburgh Supercomputing Center and the National Cancer Institute Supercomputing Center for access to resources. LGP thanks the National Institutes of Health for HL-06350 and the National Institute of Environmental Health Sciences (NIEHS) for access to their facilities.

Many-body effects in molecular dynamics simulations of Na +(H2O)n and Cl-(H2O) n clusters

Many‐body effects were examined in a series of molecular dynamics computer simulations on the ionic aqueous clusters Na+(H2O)n (n=4,5,6,14) and Cl−(H2O)n (n=4,5,6,7,8,14). Two potential models were used in the simulations. In one model (TIP4P) the potential was pairwise additive, while in the second model (SPCE/POL) the many body effects were explicitly included through a self‐consistent polarization routine. The two models produce equilibrium structures which are significantly different in energy and geometry. The SPCE/POL model consistently predicts energetically more stable products. In addition, for the anion cluster systems the SPCE/POL model places the Cl− on the surface of the water cluster.

Towards accurate solvation dynamics of divalent cations in water using the polarizable amoeba force field: From energetics to structure

Molecular dynamics simulations were performed using a modified amoeba force field to determine hydration and dynamical properties of the divalent cations Ca2+ and Mg2+. The extension of amoeba to divalent cations required the introduction of a cation specific parametrization. To accomplish this, the Thole polarization damping model parametrization was modified based on the ab initio polarization energy computed by a constrained space orbital variation energy decomposition scheme. Excellent agreement has been found with condensed phase experimental results using parameters derived from gas phase ab initio calculations. Additionally, we have observed that the coordination of the calcium cation is influenced by the size of the periodic water box, a recurrent issue in first principles molecular dynamics studies.

Effect of the treatment of long‐range forces on the dynamics of ions in aqueous solutions

The goal of the present work is to study the dependence of the limiting ionic mobility of such anions as fluoride, chloride, and bromide in water on the way the long‐range forces are treated in the computer simulations. With this in mind we have performed molecular dynamics computer simulations where the long‐range electrostatic forces were treated using: (a) simple truncation procedure, (b) energy switching procedure, (c) reaction field method, and (d) Ewald summation technique. Our analysis shows that the switching procedure with the short‐range switching function introduces artifacts into the simulations. These artifacts are responsible for the faster decay and oscillations in the velocity autocorrelation function of the ions and therefore for the lower value of the diffusion coefficients.

Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis

Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection.

Dephosphorylation of Threonine 38 Is Required for Nuclear Translocation and Activation of Human Xenobiotic Receptor CAR (NR1I3)

Upon activation by therapeutics, the nuclear xenobiotic/ constitutive active/androstane receptor (CAR) regulates various liver functions ranging from drug metabolism and excretion to energy metabolism. CAR can also be a risk factor for developing liver diseases such as hepatocellular carcinoma. Here we have characterized the conserved threonine 38 of human CAR as the primary residue that regulates nuclear translocation and activation of CAR. Protein kinase C phosphorylates threonine 38 located on the α-helix spanning from residues 29–42 that constitutes a part of the first zinc finger and continues into the region between the zinc fingers. Molecular dynamics study has revealed that this phosphorylation may destabilize this helix, thereby inactivating CAR binding to DNA as well as sequestering it in the cytoplasm. We have found, in fact, that helix-stabilizing mutations reversed the effects of phosphorylation. Immunohistochemical study using an anti-phospho-threonine 38 peptide antibody has, in fact, demonstrated that the classic CAR activator phenobarbital dephosphorylates the corresponding threonine 48 of mouse CAR in the cytoplasm of mouse liver and translocates CAR into the nucleus. These results define CAR as a cell signal-regulated constitutive active nuclear receptor. These results also provide phosphorylation/dephosphorylation of the threonine as the primary drug target for CAR activation.

Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling

The epidermal growth factor receptor is an unexpected target of the barbiturate phenobarbital. Antagonistic Activation Phenobarbital stimulates the transcription of genes in the liver that encode drug metabolism enzymes by indirectly stimulating the constitutive active androstane receptor (CAR). Mutoh et al. identified epidermal growth factor receptor (EGFR) as a cell surface binding target of phenobarbital. Phenobarbital bound to EGFR and blocked the binding of the ligand EGF, thereby preventing the activation of EGFR. This inhibition of EGFR promoted the activation of CAR. Molecular simulation predicted that phenobarbital and EGF share binding sites on EGFR. Together, the findings indicate that phenobarbital stimulates the nuclear activity of CAR by inhibiting the activity of EGFR at the cell surface. Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr52, which then promoted the dephosphorylation of CAR at Thr38 by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR.

Dynamics of ion solvation in a Stockmayer fluid

Molecular dynamics computer simulations were performed to study the dynamics of the ionic solvation in a Stockmayer fluid. The simulations show that the solvent relaxation proceeds in two time regimes. Most of the relaxation occurs in a short time period during which the relaxation process can be described by a Gaussian function. The long time regime can be described by an exponential relaxation. The decay exponent of the relaxation function in this regime is the same as the exponent describing the decay of the single dipole correlation function. In addition, the contribution of the rotational and translational modes of the solvent to the energy relaxation was investigated. It was found that when the rotational mode is the dominant mode of the solvent motion the relaxation occurs from the outside–in, in accordance with the Onsager ‘‘snowball’’ picture. When the influence of the translational mode is increased the Onsager picture breaks down.

STRUCTURES OF CL-(H2O)N AND F-(H2O)N (N=2,3,...,15) CLUSTERS. MOLECULAR DYNAMICS COMPUTER SIMULATIONS

We have performed molecular dynamics calculations on Cl−(H2O)n and F−(H2O)n (n=2,3,...,15) clusters. The calculations show that the F− ion is solvated in these clusters, while Cl− remains attached to the water in the clusters. We also obtained the minimum energy structures for the Cl−(H2O)n and F−(H2O)n (n=6,7,8) clusters. From the comparison of these structures with the dynamical structures we conclude that the solvation of the F− ion is due to the entropy effect.