Computer simulation of protein systems

Ligand binding to dihydrofolate reductase (DHFR) is discussed. This is an extremely important enzyme, as it is the target of several drugs (inhibitors) which are used clinically as antibacterials, antiprotozoals and in cancer chemotherapy. DHFR catalyzes the NADPH (reduced nicotinamide adenine dinucleotide phosphate) dependent reduction of dihydrofolate to tetrahydrofolate, which is used in several pathways of purine and pyrimidine iosynthesis, including that of thymidylate. Since DNA synthesis is dependent on a continuing supply of thymidylate, a blockade of DHFR resulting in a depletion of thymidylate can lead to the cessation of growth of a rapidly proliferating cell line. DHFR exhibits a significant species to species variability in its sensitivity to various inhibitors. For example, trimethoprim, an inhibitor of DHFR, binds to bacterial DHFR's 5 orders of magnitude greater than to vertebrate DHFR's. The structural mechanics, dynamics and energetics of a family of dihydrofolate reductases are studied to rationalize the basis for the inhibitor of these enyzmes and to understand the molecular basis of the difference in the binding constants between the species. This involves investigating the conformational changes induced in the protein on binding the ligand, the internal strain imposed by the enzyme on the ligand, the restriction of fluctuations in atom positions due to binding and the consequent change in entropy

Helicity Dependent and Independent Generalized Parton Distributions of the Nucleon in Lattice QCD

A complete description of the nucleon structure in terms of generalized parton distributions (GPDs) at twist 2 level requires the measurement/computation of the eight functions H, E, \tilde H, \tilde E, H_T, E_T, \tilde H_T and \tilde E_T, all depending on the three variables x, \xi and t. In this talk, we present and discuss our first steps in the framework of lattice QCD towards this enormous task. Dynamical lattice QCD results for the lowest three Mellin moments of the helicity dependent and independent GPDs are shown in terms of their corresponding generalized form factors. Implications for the transverse coordinate space structure of the nucleon as well as the orbital angular momentum (OAM) contribution of quarks to the nucleon spin are discussed in some detail.Comment: 5 pages, 5 figures, Talk presented by Ph.H. at Electron-Nucleus Scattering VIII, Elba, Italy, June 21-25, 2004; typos corrected, minor change in wording on p.4&

Signal processing in local neuronal circuits based on activity-dependent noise and competition

We study the characteristics of weak signal detection by a recurrent neuronal network with plastic synaptic coupling. It is shown that in the presence of an asynchronous component in synaptic transmission, the network acquires selectivity with respect to the frequency of weak periodic stimuli. For non-periodic frequency-modulated stimuli, the response is quantified by the mutual information between input (signal) and output (network's activity), and is optimized by synaptic depression. Introducing correlations in signal structure resulted in the decrease of input-output mutual information. Our results suggest that in neural systems with plastic connectivity, information is not merely carried passively by the signal; rather, the information content of the signal itself might determine the mode of its processing by a local neuronal circuit.Comment: 15 pages, 4 pages, in press for "Chaos

Transverse Structure of Nucleon Parton Distributions from Lattice QCD

This work presents the first calculation in lattice QCD of three moments of spin-averaged and spin-polarized generalized parton distributions in the proton. It is shown that the slope of the associated generalized form factors decreases significantly as the moment increases, indicating that the transverse size of the light-cone quark distribution decreases as the momentum fraction of the struck parton increases.Comment: 4 pages, 1 figur

Calculation of the nucleon axial charge in lattice QCD

Protons and neutrons have a rich structure in terms of their constituents, the quarks and gluons. Understanding this structure requires solving Quantum Chromodynamics (QCD). However QCD is extremely complicated, so we must numerically solve the equations of QCD using a method known as lattice QCD. Here we describe a typical lattice QCD calculation by examining our recent computation of the nucleon axial charge.Comment: Prepared for Scientific Discovery through Advanced Computing (SciDAC 2006), Denver, Colorado, June 25-29 200

Nucleon structure in the chiral regime with domain wall fermions on an improved staggered sea

Moments of unpolarized, helicity, and transversity distributions, electromagnetic form factors, and generalized form factors of the nucleon are presented from a preliminary analysis of lattice results using pion masses down to 359 MeV. The twist two matrix elements are calculated using a mixed action of domain wall valence quarks and asqtad staggered sea quarks and are renormalized perturbatively. Several observables are extrapolated to the physical limit using chiral perturbation theory. Results are compared with experimental moments of quark distributions and electromagnetic form factors and phenomenologically determined generalized form factors, and the implications on the transverse structure and spin content of the nucleon are discussed.Comment: Talks of J.W. Negele and D.B. Renner at Lattice 200

Generalized Parton Distributions in Full Lattice QCD

We present recent results on generalized parton distributions from dynamical lattice QCD calculations. Our set of twelve different combinations of couplings and quark masses allows for a preliminary study of the pion mass dependence of the transverse nucleon structure.Comment: 8 pages, 5 figures; Talk presented by Ph.H. at Light-Cone 2004, Amsterdam, 16 - 20 Augus

Two-dimensional echocardiographic spectrum of univentricular atrioventricular connection

The spectrum of anomalies in hearts having a univentricular atrioventricular (AV) connection was examined by two-dimensional echocardiography in 183 patients and the anatomic findings were compared with angiography. The mode of AV connection was found to be of three types: 1) double inletvia two A V valves; 2) singleinlet via one AV valve with absence of the other (left or right AV valve atresia); and 3) common inletvia a common AV valve. Identification of an accessory chamber by two-dimensional echocardiography was possible with 90% sensitivity, but it was limited compared with angiography in patients with severely hypoplastic anterior Chambers and pulmonary valve atresia. All patients with subaortic outlet foramen obstruction were detected. Great artery position and the presence of obstruction to pulmonary flow were correctly predicted in all but one patient. Two-dimensional echocardiography was superior to angiography for the detection of AV valve abnormalities which were present in 27% and included abnormal chordae, hypoplasia or dysplasia of either valve. Two-dimensional echocardiography should play an essential role in the complete preoperative assessment of patients with univentricular AV connection

Nucleon Electromagnetic Form Factors from Lattice QCD using 2+1 Flavor Domain Wall Fermions on Fine Lattices and Chiral Perturbation Theory

We present a high-statistics calculation of nucleon electromagnetic form factors in $N_f=2+1$ lattice QCD using domain wall quarks on fine lattices, to attain a new level of precision in systematic and statistical errors. Our calculations use $32^3 \times 64$ lattices with lattice spacing a=0.084 fm for pion masses of 297, 355, and 403 MeV, and we perform an overdetermined analysis using on the order of 3600 to 7000 measurements to calculate nucleon electric and magnetic form factors up to $Q^2 \approx$ 1.05 GeV$^2$. Results are shown to be consistent with those obtained using valence domain wall quarks with improved staggered sea quarks, and using coarse domain wall lattices. We determine the isovector Dirac radius $r_1^v$, Pauli radius $r_2^v$ and anomalous magnetic moment $\kappa_v$. We also determine connected contributions to the corresponding isoscalar observables. We extrapolate these observables to the physical pion mass using two different formulations of two-flavor chiral effective field theory at one loop: the heavy baryon Small Scale Expansion (SSE) and covariant baryon chiral perturbation theory. The isovector results and the connected contributions to the isoscalar results are compared with experiment, and the need for calculations at smaller pion masses is discussed.Comment: 44 pages, 40 figure