https://users.cs.duke.edu/~brd/Teaching/Bio/asmb/current/Papers/Lit4Docking/Gold_dock.pdf

Development and validation of a genetic algorithm for flexible docking.

Fourier transform ir (FTIR) spectra of 21 globular proteins have been obtained at 2 cm−1 resolution from 1600 to 1700 cm−1 in deuterium oxide solution. Fourier self-deconvolution was applied to all spectra, revealing that the amide I band of each protein except casein consists of six to nine components. The components are observed at 11 well-defined frequencies, although all proteins do not exhibit components at every characteristic frequency. The root mean square (RMS) deviation of 124 individual values from the 11 average characteristic frequencies is 1.9 cm−1. The observed components are assigned to helical segments, extended beta-segments, unordered segments, and turns. Segments with similar structures do not necessarily exhibit band components with identical frequencies. For instance, the lower frequency beta-structure band can vary within a range of approximately 15 cm−1. The relative areas of the individual components of the deconvolved spectra were determined by a Gauss–Newton, iterative curve-fitting procedure that assumed Gaussian band envelopes for the deconvolved components. The measured areas were used to estimate the percentage of helix and beta-structure for each of 21 globular proteins. The results are in good general agreement with values derived from x-ray data by Levitt and Greer. The RMS deviation between 22 values (alpha- and beta-content of 11 beta-rich proteins measured by both techniques) is 2.5 percentage points; the maximum absolute deviation is 4 percentage points.

Examination of the secondary structure of proteins by deconvolved FTIR spectra.

A wealth of protein and DNA sequence data is being generated by genome projects and other sequencing efforts. A crucial barrier to deciphering these sequences and understanding the relations among them is the difficulty of detecting subtle local residue patterns common to multiple sequences. Such patterns frequently reflect similar molecular structures and biological properties. A mathematical definition of this "local multiple alignment" problem suitable for full computer automation has been used to develop a new and sensitive algorithm, based on the statistical method of iterative sampling. This algorithm finds an optimized local alignment model for N sequences in N-linear time, requiring only seconds on current workstations, and allows the simultaneous detection and optimization of multiple patterns and pattern repeats. The method is illustrated as applied to helix-turn-helix proteins, lipocalins, and prenyltransferases.

/pdf/detecting-subtle-sequence-signals-a-gibbs-sampling-strategy-56bu9neqln.pdf

Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment

DeepMind presented notably accurate predictions at the recent 14th Critical Assessment of Structure Prediction (CASP14) conference. We explored network architectures that incorporate related ideas and obtained the best performance with a three-track network in which information at the one-dimensional (1D) sequence level, the 2D distance map level, and the 3D coordinate level is successively transformed and integrated. The three-track network produces structure predictions with accuracies approaching those of DeepMind in CASP14, enables the rapid solution of challenging x-ray crystallography and cryo-electron microscopy structure modeling problems, and provides insights into the functions of proteins of currently unknown structure. The network also enables rapid generation of accurate protein-protein complex models from sequence information alone, short-circuiting traditional approaches that require modeling of individual subunits followed by docking. We make the method available to the scientific community to speed biological research.

/pdf/accurate-prediction-of-protein-structures-and-interactions-nw6sw2famm.pdf

Accurate prediction of protein structures and interactions using a three-track neural network

Polyubiquitin chains linked through Lys48 are the principal signal for targeting substrates to the 26S proteasome. Through studies of structurally defined, polyubiquitylated model substrates, we show that tetraubiquitin is the minimum signal for efficient proteasomal targeting. The mechanism of targeting involves a simple increase in substrate affinity that is brought about by autonomous binding of the polyubiquitin chain. Assigning the proteasomal signaling function to a specific polymeric unit explains how a single ubiquitin can act as a functionally distinct signal, for example in endocytosis. The properties of the substrates studied here implicate substrate unfolding as a kinetically dominant step in the proteolysis of properly folded proteins, and suggest that extraproteasomal chaperones are required for efficient degradation of certain proteasome substrates.

/pdf/recognition-of-the-polyubiquitin-proteolytic-signal-4liap3bh27.pdf

Recognition of the polyubiquitin proteolytic signal.

Since its first isolation1, bovine β-lactoglobulin (BLG) has been an enigma: although it is abundant in the whey fraction of milk, its function is still not clear. The results of the many physicochemical studies on the protein need a structural interpretation. We report here the structure of the orthorhombic crystal form of cow BLG at pH 7.6, at a resolution of 2.8 A. It has an unusual protein fold, composed of two slabs of antiparallel β-sheet, which shows a remarkable similarity to plasma retinol-binding protein. A possible binding site for retinol in BLG has been identified by model-building. This suggests a role for BLG in vitamin A transport and we have discovered specific receptors for the BLG–retinol complex in the intestine of neonate calves.

The structure of β -lactoglobulin and its similarity to plasma retinol-binding protein

The lipocalin protein family: structural and sequence overview.

Bovine β-lactoglobulin at 1.8 Å resolution — still an enigmatic lipocalin

THE principal protein excreted in male rat urine, urinary α2-globulin and the homologous mouse protein, major urinary protein, have been well characterized, although their functions remain unclear. Male rat urine affects the behaviour and sexual response of female rats1, leading to the proposal that rodent urinary proteins are responsible for binding pheromones and their subsequent release from drying urine2. Urinary α2-globulin is also involved in hyaline droplet nephropathy, an important toxicological syndrome in male rats resulting from exposure to a number of industrial chemicals and characterized by the accumulation of liganded urinary α2-globulin in lysosomes in the kidney, followed by the induction of renal cancer3. We now report the three-dimensional structures of mouse major urinary protein (at 2.4 A resolution) and rat urinary α2-globulin (at 2.8 A resolution). The results corroborate the role of these proteins in pheromone transport and elaborate the structural basis of ligand binding.

Pheromone binding to two rodent urinary proteins revealed by X-ray crystallography.

The lipocalins and fatty acid-binding proteins (FABPs) are two recently identified protein families that both function by binding small hydrophobic molecules. We have sought to clarify relationships within and between these two groups through an analysis of both structure and sequence. Within a similar overall folding pattern, we find large parts of the lipocalin and FABP structures to be quantitatively equivalent. The three largest structurally conserved regions within the lipocalin common core correspond to characteristic sequence motifs that we have used to determine the constitution of this family using an iterative sequence analysis procedure. This afforded a new interpretation of the family, which highlighted the difficulties of determining a comprehensive and coherent classification of the lipocalins. The first of the three conserved sequence motifs is also common to the FABPs and corresponds to a conserved structural element characteristic of both families. Similarities of structure and sequence within the two families suggests that they form part of a larger "structural superfamily"; we have christened this overall group the calycins to reflect the cup-shaped structure of its members.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/pro.5560020507

Anthony C.T. North

Papers

The structure of β -lactoglobulin and its similarity to plasma retinol-binding protein

The lipocalin protein family: structural and sequence overview.

Bovine β-lactoglobulin at 1.8 Å resolution — still an enigmatic lipocalin

Pheromone binding to two rodent urinary proteins revealed by X-ray crystallography.

Structure and sequence relationships in the lipocalins and related proteins.