Combining intracellular selection with protein-fragment complementation to derive A interacting peptides

Aggregation of the β-amyloid (Aβ) peptide into toxic oligomers is considered the primary event in the pathogenesis of Alzheimer's disease. Previously generated peptides and mimetics designed to bind to amyloid fibrils have encountered problems in solubility, protease susceptibility and the population of small soluble toxic oligomers oligomers. We present a new method that opens the possibility of deriving new amyloid inhibitors. The intracellular protein-fragment complementation assay (PCA) approach uses a semi-rational design approach to generate peptides capable of binding to Aβ. Peptide libraries are based on Aβ regions responsible for instigating amyloidosis, with screening and selection occurring entirely inside Escherichia coli. Successfully selected peptides must therefore bind Aβ and recombine an essential enzyme while permitting bacterial cell survival. No assumptions are made regarding the mechanism of action for selected binders. Biophysical characterisation demonstrates that binding induces a noticeable reduction in amyloid. Therefore, this amyloid-PCA approach may offer a new pathway for the design of effective inhibitors against the formation of amyloid in general

The Grassmannian Origin Of Dual Superconformal Invariance

A dual formulation of the S Matrix for N=4 SYM has recently been presented, where all leading singularities of n-particle N^{k-2}MHV amplitudes are given as an integral over the Grassmannian G(k,n), with cyclic symmetry, parity and superconformal invariance manifest. In this short note we show that the dual superconformal invariance of this object is also manifest. The geometry naturally suggests a partial integration and simple change of variable to an integral over G(k-2,n). This change of variable precisely corresponds to the mapping between usual momentum variables and the "momentum twistors" introduced by Hodges, and yields an elementary derivation of the momentum-twistor space formula very recently presented by Mason and Skinner, which is manifestly dual superconformal invariant. Thus the G(k,n) Grassmannian formulation allows a direct understanding of all the important symmetries of N=4 SYM scattering amplitudes.Comment: 9 page

New differential equations for on-shell loop integrals

We present a novel type of differential equations for on-shell loop integrals. The equations are second-order and importantly, they reduce the loop level by one, so that they can be solved iteratively in the loop order. We present several infinite series of integrals satisfying such iterative differential equations. The differential operators we use are best written using momentum twistor space. The use of the latter was advocated in recent papers discussing loop integrals in N=4 super Yang-Mills. One of our motivations is to provide a tool for deriving analytical results for scattering amplitudes in this theory. We show that the integrals needed for planar MHV amplitudes up to two loops can be thought of as deriving from a single master topology. The master integral satisfies our differential equations, and so do most of the reduced integrals. A consequence of the differential equations is that the integrals we discuss are not arbitrarily complicated transcendental functions. For two specific two-loop integrals we give the full analytic solution. The simplicity of the integrals appearing in the scattering amplitudes in planar N=4 super Yang-Mills is strongly suggestive of a relation to the conjectured underlying integrability of the theory. We expect these differential equations to be relevant for all planar MHV and non-MHV amplitudes. We also discuss possible extensions of our method to more general classes of integrals.Comment: 39 pages, 8 figures; v2: typos corrected, definition of harmonic polylogarithms adde

Unification of Residues and Grassmannian Dualities

The conjectured duality relating all-loop leading singularities of n-particle N^(k-2)MHV scattering amplitudes in N=4 SYM to a simple contour integral over the Grassmannian G(k,n) makes all the symmetries of the theory manifest. Every residue is individually Yangian invariant, but does not have a local space-time interpretation--only a special sum over residues gives physical amplitudes. In this paper we show that the sum over residues giving tree amplitudes can be unified into a single algebraic variety, which we explicitly construct for all NMHV and N^2MHV amplitudes. Remarkably, this allows the contour integral to have a "particle interpretation" in the Grassmannian, where higher-point amplitudes can be constructed from lower-point ones by adding one particle at a time, with soft limits manifest. We move on to show that the connected prescription for tree amplitudes in Witten's twistor string theory also admits a Grassmannian particle interpretation, where the integral over the Grassmannian localizes over the Veronese map from G(2,n) to G(k,n). These apparently very different theories are related by a natural deformation with a parameter t that smoothly interpolates between them. For NMHV amplitudes, we use a simple residue theorem to prove t-independence of the result, thus establishing a novel kind of duality between these theories.Comment: 56 pages, 11 figures; v2: typos corrected, minor improvement

On All-loop Integrands of Scattering Amplitudes in Planar N=4 SYM

We study the relationship between the momentum twistor MHV vertex expansion of planar amplitudes in N=4 super-Yang-Mills and the all-loop generalization of the BCFW recursion relations. We demonstrate explicitly in several examples that the MHV vertex expressions for tree-level amplitudes and loop integrands satisfy the recursion relations. Furthermore, we introduce a rewriting of the MHV expansion in terms of sums over non-crossing partitions and show that this cyclically invariant formula satisfies the recursion relations for all numbers of legs and all loop orders.Comment: 34 pages, 17 figures; v2: Minor improvements to exposition and discussion, updated references, typos fixe

The Yangian origin of the Grassmannian integral

In this paper we analyse formulas which reproduce different contributions to scattering amplitudes in N=4 super Yang-Mills theory through a Grassmannian integral. Recently their Yangian invariance has been proved directly by using the explicit expression of the Yangian level-one generators. The specific cyclic structure of the form integrated over the Grassmannian enters in a crucial way in demonstrating the symmetry. Here we show that the Yangian symmetry fixes this structure uniquely.Comment: 26 pages. v2: typos corrected, published versio

The one-loop six-dimensional hexagon integral and its relation to MHV amplitudes in N=4 SYM

We provide an analytic formula for the (rescaled) one-loop scalar hexagon integral $\tilde\Phi_6$ with all external legs massless, in terms of classical polylogarithms. We show that this integral is closely connected to two integrals appearing in one- and two-loop amplitudes in planar $\\mathcal{N}=4$ super-Yang-Mills theory, $\Omega^{(1)}$ and $\Omega^{(2)}$. The derivative of $\Omega^{(2)}$ with respect to one of the conformal invariants yields $\tilde\Phi_6$, while another first-order differential operator applied to $\tilde\Phi_6$ yields $\Omega^{(1)}$. We also introduce some kinematic variables that rationalize the arguments of the polylogarithms, making it easy to verify the latter differential equation. We also give a further example of a six-dimensional integral relevant for amplitudes in $\\mathcal{N}=4$ super-Yang-Mills.Comment: 18 pages, 2 figure

Local Spacetime Physics from the Grassmannian

A duality has recently been conjectured between all leading singularities of n-particle N^(k-2)MHV scattering amplitudes in N=4 SYM and the residues of a contour integral with a natural measure over the Grassmannian G(k,n). In this note we show that a simple contour deformation converts the sum of Grassmannian residues associated with the BCFW expansion of NMHV tree amplitudes to the CSW expansion of the same amplitude. We propose that for general k the same deformation yields the (k-2) parameter Risager expansion. We establish this equivalence for all MHV-bar amplitudes and show that the Risager degrees of freedom are non-trivially determined by the GL(k-2) "gauge" degrees of freedom in the Grassmannian. The Risager expansion is known to recursively construct the CSW expansion for all tree amplitudes, and given that the CSW expansion follows directly from the (super) Yang-Mills Lagrangian in light-cone gauge, this contour deformation allows us to directly see the emergence of local space-time physics from the Grassmannian.Comment: 22 pages, 13 figures; v2: minor updates, typos correcte

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases