Two-point correlation function for Dirichlet L-functions

The two-point correlation function for the zeros of Dirichlet L-functions at a height E on the critical line is calculated heuristically using a generalization of the Hardy-Littlewood conjecture for pairs of primes in arithmetic progression. The result matches the conjectured Random-Matrix form in the limit as $E\rightarrow\infty$ and, importantly, includes finite-E corrections. These finite-E corrections differ from those in the case of the Riemann zeta-function, obtained in (1996 Phys. Rev. Lett. 77 1472), by certain finite products of primes which divide the modulus of the primitive character used to construct the L-function in question.Comment: 10 page

A method for calculating spectral statistics based on random-matrix universality with an application to the three-point correlations of the Riemann zeros

We illustrate a general method for calculating spectral statistics that combines the universal (Random Matrix Theory limit) and the non-universal (trace-formula-related) contributions by giving a heuristic derivation of the three-point correlation function for the zeros of the Riemann zeta function. The main idea is to construct a generalized Hermitian random matrix ensemble whose mean eigenvalue density coincides with a large but finite portion of the actual density of the spectrum or the Riemann zeros. Averaging the random matrix result over remaining oscillatory terms related, in the case of the zeta function, to small primes leads to a formula for the three-point correlation function that is in agreement with results from other heuristic methods. This provides support for these different methods. The advantage of the approach we set out here is that it incorporates the determinental structure of the Random Matrix limit.Comment: 22 page

Calibration of the spin-scan ozone imager aboard the dynamics Explorer 1 satellite

The calibration technique, which contains the calibrated backscattered radiance values necessary for performing the calibrations, is presented. The calibration constants for September to October 1981 to determine total columnar ozone from the Spin-Scan Ozone Imager (SOI), which is a part of the auroral imaging instrumentation aboard the Dynamics Explorer 1 Satellite, are provided. The precision of the SOI-derived total columnar ozone is estimated to be better than 2.4 percent. Linear regression analysis was used to calculate correlation coefficients between total columnar ozone obtained from Dobson ground stations and SOI which indicate that the SOI total columnar ozone determination is equally accurate for clear or cloudy weather conditions

Protein binding specificity versus promiscuity

Interactions between macromolecules in general, and between proteins in particular, are essential for any life process. Examples include transfer of information, inhibition or activation of function, molecular recognition as in the immune system, assembly of macromolecular structures and molecular machines, and more. Proteins interact with affinities ranging from millimolar to femtomolar and, because affinity determines the concentration required to obtain 50% binding, the amount of different complexes formed is very much related to local concentrations. Although the concentration of a specific binding partner is usually quite low in the cell (nanomolar to micromolar), the total concentration of other macromolecules is very high, allowing weak and non-specific interactions to play important roles. In this review we address the question of binding specificity, that is, how do some proteins maintain monogamous relations while others are clearly polygamous. We examine recent work that addresses the molecular and structural basis for specificity versus promiscuity. We show through examples how multiple solutions exist to achieve binding via similar interfaces and how protein specificity can be tuned using both positive and negative selection (specificity by demand). Binding of a protein to numerous partners can be promoted through variation in which residues are used for binding, conformational plasticity and/or post-translational modification. Natively unstructured regions represent the extreme case in which structure is obtained only upon binding. Many natively unstructured proteins serve as hubs in protein–protein interaction networks and such promiscuity can be of functional importance in biology.National Institutes of Health (U.S.) (Award GM084181)National Institutes of Health (U.S.) (Award GM067681

Locating Herpesvirus Bcl-2 Homologs in the Specificity Landscape of Anti-Apoptotic Bcl-2 Proteins

Viral homologs of the anti-apoptotic Bcl-2 proteins are highly diverged from their mammalian counterparts, yet they perform overlapping functions by binding and inhibiting BH3 (Bcl-2 homology 3)-motif-containing proteins. We investigated the BH3 binding properties of the herpesvirus Bcl-2 homologs KSBcl-2, BHRF1, and M11, as they relate to those of the human Bcl-2 homologs Mcl-1, Bfl-1, Bcl-w, Bcl-xL, and Bcl-2. Analysis of the sequence and structure of the BH3 binding grooves showed that, despite low sequence identity, M11 has structural similarities to Bcl-xL, Bcl-2, and Bcl-w. BHRF1 and KSBcl-2 are more structurally similar to Mcl-1 than to the other human proteins. Binding to human BH3-like peptides showed that KSBcl-2 has similar specificity to Mcl-1, and BHRF1 has a restricted binding profile; M11 binding preferences are distinct from those of Bcl-xL, Bcl-2, and Bcl-w. Because KSBcl-2 and BHRF1 are from human herpesviruses associated with malignancies, we screened computationally designed BH3 peptide libraries using bacterial surface display to identify selective binders of KSBcl-2 or BHRF1. The resulting peptides bound to KSBcl-2 and BHRF1 in preference to Bfl-1, Bcl-w, Bcl-xL, and Bcl-2 but showed only modest specificity over Mcl-1. Rational mutagenesis increased specificity against Mcl-1, resulting in a peptide with a dissociation constant of 2.9 nM for binding to KSBcl-2 and > 1000-fold specificity over other Bcl-2 proteins, as well as a peptide with > 70-fold specificity for BHRF1. In addition to providing new insights into viral Bcl-2 binding specificity, this study will inform future work analyzing the interaction properties of homologous binding domains and designing specific protein interaction partners.National Institute of General Medical Sciences (U.S.) (R01GM110048)National Science Foundation (U.S.) (0821391

Designing helical peptide inhibitors of protein–protein interactions

Short helical peptides combine characteristics of small molecules and large proteins and provide an exciting area of opportunity in protein design. A growing number of studies report novel helical peptide inhibitors of protein-protein interactions. New techniques have been developed for peptide design and for chemically stabilizing peptides in a helical conformation, which frequently improves protease resistance and cell permeability. We summarize advances in peptide crosslinking chemistry and give examples of peptide design studies targeting coiled-coil transcription factors, Bcl-2 family proteins, MDM2/MDMX, and HIV gp41, among other targets.National Institute of General Medical Sciences (U.S.) (Award GM067681)National Institute of General Medical Sciences (U.S.) (Award GM110048)National Institute of General Medical Sciences (U.S.) (Award GM084181