From HIV protein sequences to viral fitness landscapes: a new paradigm for in silico vaccine design

Background: An inexpensive prophylactic vaccine offers the best hope to curb the HIV/AIDS epidemic gripping sub-Saharan Africa. Systematic means to guide the design of an effective immunogen for this, and other, infectious diseases are not available. What is required is a method to chart the peaks and valleys of viral fitness as a function of amino acid sequence. An efficacious vaccine would eject the virus from the high fitness peaks, and drive it into the valleys where its compromised fitness impairs its ability to replicate and inflict damage to the host. Methods: Appealing to spin glass models in statistical physics, we present a novel approach to translate viral sequence databases into landscapes of viral fitness. These inferred models furnish a quantitative description of viral replicative capacity as a function of amino acid sequence. We illustrate this approach in the development of landscapes for the proteins of HIV-1 clade B Gag. Results: In comparisons to experimental and clinical data, our inferred landscapes demonstrate excellent agreement with: 1) in vitro replicative fitness measurements, 2) clinically observed high-fitness circulating viral strains, 3) documented HLA associated CTL escape mutations, and 4) intra-host temporal adaptation pathways revealed by deep sequencing. These favorable comparisons support our landscapes as reflections of intrinsic viral fitness. We illustrate the value of such descriptions in the computational design of a CTL Gag immunogen. Conclusion: We present a novel methodology to translate viral sequence data into quantitative landscapes of viral fitness. In an application to HIV-1 Gag, we illustrate excellent agreement of our model predictions with experimental and clinical data, and demonstrate a powerful new approach for HIV immunogen design. We anticipate that this approach may represent a heretofore unprecedented means to synthesize fitness landscapes for diverse pathogens, and may provide the basis for the design of improved prophylactic and therapeutic strategies

Static displacements and chemical correlations in alloys

Recent experiments in metallic solid solutions have revealed interesting correlations between static pair-displacements and the ordering behavior of these alloys. This paper discusses a simple theoretical model which successfully explains these observations and which provides a natural framework for analyzing experimental measurements of pair-displacements and chemical correlations in solid solutions. The utility and scope of this model is demonstrated by analyzing results of experiments on $Ni-Fe$ and $Cr-Fe$ alloys and results of simulations of $Cu-Au$ and $Cu-Ag$ alloys.Comment: 12 page

A Fermi Fluid Description of the Half-Filled Landau Level

We present a many-body approach to calculate the ground state properties of a system of electrons in a half-filled Landau level. Our starting point is a simplified version of the recently proposed trial wave function where one includes the antisymmetrization operator to the bosonic Laughlin state. Using the classical plasma analogy, we calculate the pair-correlation function, the static structure function and the ground state energy in the thermodynamic limit. These results are in good agreement with the expected behavior at $\nu=\frac12$.Comment: 4 pages, REVTEX, and 4 .ps file

Generalised Einstein Relation for Hot Brownian Motion

The Brownian motion of a hot nanoparticle is described by an effective Markov theory based on fluctuating hydrodynamics. Its predictions are scrutinized over a wide temperature range using large-scale molecular dynamics simulations of a hot nanoparticle in a Lennard-Jones fluid. The particle positions and momenta are found to be Boltzmann distributed according to distinct effective temperatures $T_\mathrm{HBM}$ and $T_\mathrm{k}$ . For $T_\mathrm{HBM}$ we derive a formally exact theoretical prediction and establish a generalised Einstein relation that links it to directly measurable quantities

Monte Carlo Study of Short-Range Order and Displacement Effects in Disordered CuAu

The correlation between local chemical environment and atomic displacements in disordered CuAu alloy has been studied using Monte Carlo simulations based on the effective medium theory (EMT) of metallic cohesion. These simulations correctly reproduce the chemically-specific nearest-neighbor distances in the random alloy across the entire Cu\$_x\$Au\$_{1-x}\$ concentration range. In the random equiatomic CuAu alloy, the chemically specific pair distances depend strongly on the local atomic environment (i.e. fraction of like/unlike nearest neighbors). In CuAu alloy with short-range order, the relationship between local environment and displacements remains qualitatively similar. However the increase in short-range order causes the average Cu-Au distance to decrease below the average Cu-Cu distance, as it does in the ordered CuAuI phase. Many of these trends can be understood qualitatively from the different neutral sphere radii and compressibilities of the Cu and Au atoms.Comment: 9 pages, 5 figures, 2 table

Dynamics of vibrational excitation in the C<SUB>60</SUB> single-molecule transistor

We investigate the vibrational excitations recently observed in the single C60 molecule transistor [Park et al., Nature (London) 47, 57 (2000)]. There can be two mechanisms for this: (a) the displacement of the equilibrium position, as the electron hops onto C60 to form C60- and (b) the position dependence of the hopping matrix element. We find that if the two electrodes are planar with the C60 sitting symmetrically between the two, then mechanism (a) is not possible, though (b) is, but the results are not in agreement with experiments. Considering C60 to be trapped between a protrusion and a flat electrode, both the mechanisms contribute and the contribution from the second can be large. For example, in the case of C60 trapped between the a protrusion and a flat electrode, the contribution can be as large as 20%. Though our results do qualitatively explain the results, for quantitative agreement with experiments, it seems necessary to consider perhaps the nonuniformity of the charge distribution in C60- caused by the image interaction or more complex electrode geometries

Dynamical Correlations in a Half-Filled Landau Level

We formulate a self-consistent field theory for the Chern-Simons fermions to study the dynamical response function of the quantum Hall system at $\nu=1/2$. Our scheme includes the effect of correlations beyond the random-phase approximation (RPA) employed to this date for this system. The resulting zero-frequency density response function vanishes as the square of the wave vector in the long-wavelength limit. The longitudinal conductivity calculated in this scheme shows linear dependence on the wave vector, like the experimentals results and the RPA, but the absolute values are higher than the experimental results.Comment: 4 pages, revtex, 3 figures included. Corrected typo