ALADYN: a web server for aligning proteins by matching their large-scale motion

The ALADYN web server aligns pairs of protein structures by comparing their internal dynamics and detecting regions that sustain similar large-scale movements. The latter often accompany functional conformational changes in proteins and enzymes. The ALADYN dynamics-based alignment can therefore highlight functionally-oriented correspondences that could be more elusive to sequence- or structure-based comparisons. The ALADYN server takes the structure files of the two proteins as input. The optimal relative positioning of the molecules is found by maximizing the similarity of the pattern of structural fluctuations which are calculated via an elastic network model. The resulting alignment is presented via an interactive graphical Java applet and is accompanied by a number of quantitative indicators and downloadable data files. The ALADYN web server is freely accessible at the http://aladyn.escience-lab.org address

Mechanical and Assembly Units of Viral Capsids Identified via Quasi-Rigid Domain Decomposition

Key steps in a viral life-cycle, such as self-assembly of a protective protein container or in some cases also subsequent maturation events, are governed by the interplay of physico-chemical mechanisms involving various spatial and temporal scales. These salient aspects of a viral life cycle are hence well described and rationalised from a mesoscopic perspective. Accordingly, various experimental and computational efforts have been directed towards identifying the fundamental building blocks that are instrumental for the mechanical response, or constitute the assembly units, of a few specific viral shells. Motivated by these earlier studies we introduce and apply a general and efficient computational scheme for identifying the stable domains of a given viral capsid. The method is based on elastic network models and quasi-rigid domain decomposition. It is first applied to a heterogeneous set of well-characterized viruses (CCMV, MS2, STNV, STMV) for which the known mechanical or assembly domains are correctly identified. The validated method is next applied to other viral particles such as L-A, Pariacoto and polyoma viruses, whose fundamental functional domains are still unknown or debated and for which we formulate verifiable predictions. The numerical code implementing the domain decomposition strategy is made freely available

Corresponding Functional Dynamics across the Hsp90 Chaperone Family: Insights from a Multiscale Analysis of MD Simulations

Understanding how local protein modifications, such as binding small-molecule ligands, can trigger and regulate large-scale motions of large protein domains is a major open issue in molecular biology. We address various aspects of this problem by analyzing and comparing atomistic simulations of Hsp90 family representatives for which crystal structures of the full length protein are available: mammalian Grp94, yeast Hsp90 and E.coli HtpG. These chaperones are studied in complex with the natural ligands ATP, ADP and in the Apo state. Common key aspects of their functional dynamics are elucidated with a novel multi-scale comparison of their internal dynamics. Starting from the atomic resolution investigation of internal fluctuations and geometric strain patterns, a novel analysis of domain dynamics is developed. The results reveal that the ligand-dependent structural modulations mostly consist of relative rigid-like movements of a limited number of quasi-rigid domains, shared by the three proteins. Two common primary hinges for such movements are identified. The first hinge, whose functional role has been demonstrated by several experimental approaches, is located at the boundary between the N-terminal and Middle-domains. The second hinge is located at the end of a three-helix bundle in the Middle-domain and unfolds/unpacks going from the ATP- to the ADP-state. This latter site could represent a promising novel druggable allosteric site common to all chaperones

PiSQRD: a web server for decomposing proteins into quasi-rigid dynamical domains

Motivation: The PiSQRD web resource can be used to subdivide protein structures in quasi-rigid dynamical domains. These domains are groups of amino acids that in the course of protein equilibrium fluctuations behave approximately as rigid bodies. The user provides as input the biomolecular structure, and specifies what fraction of protein internal fluctuation should be captured by the rigid body motion of the domains; the web server returns an interactive graphical representation of the optimal grouping of the amino acids in the number of domains satisfying the required mobility constraint. Availability: The PiSQRD web server is available free of charge for academic users at the address: http://pisqrd.escience-lab.org . Interactive visualization of the results requires

Structure of the neurotoxic complex vipoxin at 1.4 Å resolution

Vipoxin is a neurotoxic postsynaptic heterodimeric complex from the venom of Vipera ammodytes meridionalis, the most toxic snake in Europe. It consists of a basic and highly toxic phospholipase A<SUB>2</SUB> and an acidic non-toxic protein inhibitor. The two polypeptide chains have the same chain length and share 62% amino-acid identity. Vipoxin is a unique example of evolution of the catalytic and toxic phospholipase A<SUB>2</SUB> functions into inhibitory and non-toxic functions. The crystal structure of the complex has been determined by the molecular-replacement method and refined to 1.4 Å resolution to an R factor of 18.2%. The complex formation decreases the accessible surface area of the two subunits by ˜1480 Å<SUP>2</SUP>, which results in a reduction of toxicity and catalytic activity. The catalytic and substrate-binding sites of the vipoxin phospholipase A<SUB>2</SUB> are identical or similar to those of other group I/II enzymes. Two 2-methyl-2,4-pentanediol molecules are present in the hydrophobic channel close to the active site. The two subunits lack calcium ions. The negatively charged Asp49 of the phospholipase A<SUB>2</SUB>, which participates in the Ca<SUP>2+</SUP>-binding sites of other snake-venom phospholipase A<SUB>2</SUB>s, is neutralized by the side chain of Lys69 from the inhibitor. Attempts have been made to identify the toxicity region and to explain the reduced catalytic activity and toxicity of the phospholipase A<SUB>2 </SUB>subunit

Crystal structure of vipoxin at 2.0 Å: an example of regulation of a toxic function generated by molecular evolution

Vipoxin is the main toxic component in the venom of the Bulgarian snake Vipera ammodytes meridionalis, the most toxic snake in Europe. Vipoxin is a complex between a toxic phospholipase A2 (PLA2) and a non-toxic protein inhibitor. The structure is of genetic interest due to the high degree of sequence homology (62%) between the two functionally different components. The structure shows that the formation of the complex in vipoxin is significantly different to that seen in many known structures of phospholipases and contradicts the assumptions made in earlier studies. The modulation of PLA2 activity is of great pharmacological interest, and the present structure will be a model for structure-based drug design