ALEPH: a network-oriented approach for the generation of fragment-based libraries and for structure interpretation

Abstract

The analysis of large structural databases reveals general features and relationships among proteins, providing useful insight. A different approach is required to characterize ubiquitous secondary‐structure elements, where flexibility is essential in order to capture small local differences. The ALEPH software is optimized for the analysis and the extraction of small protein folds by relying on their geometry rather than on their sequence. The annotation of the structural variability of a given fold provides valuable information for fragment‐based molecular‐replacement methods, in which testing alternative model hypotheses can succeed in solving difficult structures when no homology models are available or are successful. ARCIMBOLDO_BORGES combines the use of composite secondary‐structure elements as a search model with density modification and tracing to reveal the rest of the structure when both steps are successful. This phasing method relies on general fold libraries describing variations around a given pattern of β‐sheets and helices extracted using ALEPH. The program introduces characteristic vectors defined from the main‐chain atoms as a way to describe the geometrical properties of the structure. ALEPH encodes structural properties in a graph network, the exploration of which allows secondary‐structure annotation, decomposition of a structure into small compact folds, generation of libraries of models representing a variation of a given fold and finally superposition of these folds onto a target structure. These functions are available through a graphical interface designed to interactively show the results of structure manipulation, annotation, fold decomposition, clustering and library generation. ALEPH can produce pictures of the graphs, structures and folds for publication purposes.

Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29

“…Interrogation of the PDB found only a few autonomously folding microdomains of a similar size, none of which were metal-ion binding and none were of a similar structure. ALEPH software 36 indicates that there are no regions of any known structure's peptide backbone that have an r.m.s.d. less that 1.6 Å with the backbone of the Zn-fingernail and in those closest in structure to the Zn-fingernail, several of the side chains always point in very different directions and none bind metal ions.…”

Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate N -Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development

“…ARCIMBOLDO uses PHASER to place individual α-helices by eLLG-guided molecular replacement ( 49 ) and then expand partial solutions with SHELXE ( 50 ) through density modification and autotracing. The search was set to locate 1 copy of an ensemble generated with an alpha version of the software ALEPH ( 51 ) The ensemble of two models represented the probable fold composed by 5 beta strands flanked by 2 alpha helices at each side and it contained the GNA1 of Saccharomyces cerevisiae (PDB id 1I21 , 19% identity to target sequence) and the acetyltransferase from Agrobacterium tumefaciens (PDB 2DXQ , 26% identity to target sequence). The ARCIMBOLDO_LITE solution was completed by SEQUENCE SLIDER ( 26 ) using side chain modeling with Scwrl4 ( 52 ), refinement with REFMAC5 ( 53 ), and expansion with SHELXE, resulting in a best trace of 120 residues with CC 31.9.…”

Fragment-based determination of a proteinase K structure from MicroED data using ARCIMBOLDO_SHREDDER

“…ARCIMBOLDO can generate libraries of secondarystructure or tertiary-structure fragment search models in multiple ways (Rodríguez et al, 2012;Medina et al, 2020). The most effective search model in ARCIMBOLDO is an -helix owing to its ubiquitous presence in protein structures, its constant geometry and its generally low B factors given its structural rigidity (Millá n, .…”