Accounting for epistatic interactions improves the functional analysis of protein structures

Motivation: The constraints under which sequence, structure and function coevolve are not fully understood. Bringing this mutual relationship to light can reveal the molecular basis of binding, catalysis and allostery, thereby identifying function and rationally guiding protein redesign. Underlying these relationships are the epistatic interactions that occur when the consequences of a mutation to a protein are determined by the genetic background in which it occurs. Based on prior data, we hypothesize that epistatic forces operate most strongly between residues nearby in the structure, resulting in smooth evolutionary importance across the structure. Methods and Results: We find that when residue scores of evolutionary importance are distributed smoothly between nearby residues, functional site prediction accuracy improves. Accordingly, we designed a novel measure of evolutionary importance that focuses on the interaction between pairs of structurally neighboring residues. This measure that we term pair-interaction Evolutionary Trace yields greater functional site overlap and better structure-based proteome-wide functional predictions. Conclusions: Our data show that the structural smoothness of evolutionary importance is a fundamental feature of the coevolution of sequence, structure and function. Mutations operate on individual residues, but selective pressure depends in part on the extent to which a mutation perturbs interactions with neighboring residues. In practice, this principle led us to redefine the importance of a residue in terms of the importance of its epistatic interactions with neighbors, yielding better annotation of functional residues, motivating experimental validation of a novel functional site in LexA and refining protein function prediction. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Structure of the first representative of Pfam family PF04016 (DUF364) reveals enolase and Rossmann-like folds that combine to form a unique active site with a possible role in heavy-metal chelation.

The crystal structure of Dhaf4260 from Desulfitobacterium hafniense DCB-2 was determined by single-wavelength anomalous diffraction (SAD) to a resolution of 2.01 Å using the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). This protein structure is the first representative of the PF04016 (DUF364) Pfam family and reveals a novel combination of two well known domains (an enolase N-terminal-like fold followed by a Rossmann-like domain). Structural and bioinformatic analyses reveal partial similarities to Rossmann-like methyltransferases, with residues from the enolase-like fold combining to form a unique active site that is likely to be involved in the condensation or hydrolysis of molecules implicated in the synthesis of flavins, pterins or other siderophores. The genome context of Dhaf4260 and homologs additionally supports a role in heavy-metal chelation

Bounding Anomalous Gauge-Boson Couplings

In this version we have corrected some minor errors in the tables, corrected typos, and added a reference. We have also updated our comparison with earlier workers. Figures are now included as uuencoded compressed tar files.Comment: 32 page

Bilocal expansion of the Borel amplitude and the hadronic tau decay width

The singular part of Borel transform of a QCD amplitude near the infrared renormalon can be expanded in terms of higher order Wilson coefficients of the operators associated with the renormalon. In this paper we observe that this expansion gives nontrivial constraints on the Borel amplitude that can be used to improve the accuracy of the ordinary perturbative expansion of the Borel amplitude. In particular, we consider the Borel transform of the Adler function and its expansion around the first infrared renormalon due to the gluon condensate. Using the next-to-leading order Wilson coefficient of the gluon condensate operator, we obtain an exact constraint on the Borel amplitude at the first IR renormalon. We then extrapolate, using judiciously chosen conformal transformations and Pade approximants, the ordinary perturbative expansion of the Borel amplitude in such a way that this constraint is satisfied. This procedure allows us to predict the $O(\alpha_s^4)$ coefficient of the Adler function, which gives a result consistent with the estimate by Kataev and Starshenko using a completely different method. We then apply this improved Borel amplitude to the tau decay width, and obtain the strong coupling constant $\alpha_s(M_Z) =0.1193 \pm 0.0007_{exp.} \pm 0.0010_{EW+CKM} \pm 0.0009_{meth.} \pm 0.0003_{evol.}$. We then compare this result with those of other resummation methods.Comment: 30 pages, 4 eps-figures, revtex; version as appears in PRD; no major changes; more careful rounding of some number

Model-Independent Global Constraints on New Physics

Using effective-lagrangian techniques we perform a systematic survey of the lowest-dimension effective interactions through which heavy physics might manifest itself in present experiments. We do not restrict ourselves to special classes of effective interactions (such as `oblique' corrections). We compute the effects of these operators on all currently well-measured electroweak observables, both at low energies and at the $Z$ resonance, and perform a global fit to their coefficients. Despite the fact that a great many operators arise in our survey, we find that most are quite strongly bounded by the current data. We use our survey to systematically identify those effective interactions which are {\it not} well-bounded by the data -- these could very well include large new-physics contributions. Our results may also be used to efficiently confront specific models for new physics with the data, as we illustrate with an example.Comment: plain TeX, 68 pages, 2 figures (postscript files appended), McGill-93/12, NEIPH-93-008, OCIP/C-93-6, UQAM-PHE-93/08, UdeM-LPN-TH-93-15

Structure of a putative NTP pyrophosphohydrolase: YP_001813558.1 from Exiguobacterium sibiricum 255-15.

The crystal structure of a putative NTPase, YP_001813558.1 from Exiguobacterium sibiricum 255-15 (PF09934, DUF2166) was determined to 1.78 Å resolution. YP_001813558.1 and its homologs (dimeric dUTPases, MazG proteins and HisE-encoded phosphoribosyl ATP pyrophosphohydrolases) form a superfamily of all-α-helical NTP pyrophosphatases. In dimeric dUTPase-like proteins, a central four-helix bundle forms the active site. However, in YP_001813558.1, an unexpected intertwined swapping of two of the helices that compose the conserved helix bundle results in a `linked dimer' that has not previously been observed for this family. Interestingly, despite this novel mode of dimerization, the metal-binding site for divalent cations, such as magnesium, that are essential for NTPase activity is still conserved. Furthermore, the active-site residues that are involved in sugar binding of the NTPs are also conserved when compared with other α-helical NTPases, but those that recognize the nucleotide bases are not conserved, suggesting a different substrate specificity

Uses and Abuses of Effective Lagrangians

Motivated by past and recent analyses we critically re-examine the use of effective lagrangians in the literature to constrain new physics and to determine the `physics reach' of future experiments. We demonstrate that many calculations, such as those involving anomalous trilinear gauge-boson couplings, either considerably overestimate loop-induced effects, or give ambiguous answers. The source of these problems is the use of cutoffs to evaluate the size of such operators in loop diagrams. In contrast to other critics of these loop estimates, we prove that the inclusion of nonlinearly-realized gauge invariance into the low-energy lagrangian is irrelevant to this conclusion. We use an explicit example using known multi-Higgs physics above the weak scale to underline these points. We show how to draw conclusions regarding the nature of the unknown high-energy physics without making reference to low-energy cutoffs.Comment: 36 page

Structure of the γ-D-glutamyl-L-diamino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-γ-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases.

Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific γ-D-glutamyl-L-diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (L-Ala-γ-D-Glu) enabled the identification of conserved sequence and structural signatures for recognition of L-Ala and γ-D-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial L-alanine-γ-D-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam