Can molecular dynamics simulations help in discriminating correct from erroneous protein 3D models?

<p>Abstract</p> <p>Background</p> <p>Recent approaches for predicting the three-dimensional (3D) structure of proteins such as <it>de novo </it>or fold recognition methods mostly rely on simplified energy potential functions and a reduced representation of the polypeptide chain. These simplifications facilitate the exploration of the protein conformational space but do not permit to capture entirely the subtle relationship that exists between the amino acid sequence and its native structure. It has been proposed that physics-based energy functions together with techniques for sampling the conformational space, e.g., Monte Carlo or molecular dynamics (MD) simulations, are better suited to the task of modelling proteins at higher resolutions than those of models obtained with the former type of methods. In this study we monitor different protein structural properties along MD trajectories to discriminate correct from erroneous models. These models are based on the sequence-structure alignments provided by our fold recognition method, FROST. We define correct models as being built from alignments of sequences with structures similar to their native structures and erroneous models from alignments of sequences with structures unrelated to their native structures.</p> <p>Results</p> <p>For three test sequences whose native structures belong to the all-<it>α</it>, all-<it>β </it>and <it>αβ </it>classes we built a set of models intended to cover the whole spectrum: from a perfect model, i.e., the native structure, to a very poor model, i.e., a random alignment of the test sequence with a structure belonging to another structural class, including several intermediate models based on fold recognition alignments. We submitted these models to 11 ns of MD simulations at three different temperatures. We monitored along the corresponding trajectories the mean of the Root-Mean-Square deviations (RMSd) with respect to the initial conformation, the RMSd fluctuations, the number of conformation clusters, the evolution of secondary structures and the surface area of residues. None of these criteria alone is 100% efficient in discriminating correct from erroneous models. The mean RMSd, RMSd fluctuations, secondary structure and clustering of conformations show some false positives whereas the residue surface area criterion shows false negatives. However if we consider these criteria in combination it is straightforward to discriminate the two types of models.</p> <p>Conclusion</p> <p>The ability of discriminating correct from erroneous models allows us to improve the specificity and sensitivity of our fold recognition method for a number of ambiguous cases.</p

Protein secondary structure assignment revisited: a detailed analysis of different assignment methods

BACKGROUND: A number of methods are now available to perform automatic assignment of periodic secondary structures from atomic coordinates, based on different characteristics of the secondary structures. In general these methods exhibit a broad consensus as to the location of most helix and strand core segments in protein structures. However the termini of the segments are often ill-defined and it is difficult to decide unambiguously which residues at the edge of the segments have to be included. In addition, there is a "twilight zone" where secondary structure segments depart significantly from the idealized models of Pauling and Corey. For these segments, one has to decide whether the observed structural variations are merely distorsions or whether they constitute a break in the secondary structure. METHODS: To address these problems, we have developed a method for secondary structure assignment, called KAKSI. Assignments made by KAKSI are compared with assignments given by DSSP, STRIDE, XTLSSTR, PSEA and SECSTR, as well as secondary structures found in PDB files, on 4 datasets (X-ray structures with different resolution range, NMR structures). RESULTS: A detailed comparison of KAKSI assignments with those of STRIDE and PSEA reveals that KAKSI assigns slightly longer helices and strands than STRIDE in case of one-to-one correspondence between the segments. However, KAKSI tends also to favor the assignment of several short helices when STRIDE and PSEA assign longer, kinked, helices. Helices assigned by KAKSI have geometrical characteristics close to those described in the PDB. They are more linear than helices assigned by other methods. The same tendency to split long segments is observed for strands, although less systematically. We present a number of cases of secondary structure assignments that illustrate this behavior. CONCLUSION: Our method provides valuable assignments which favor the regularity of secondary structure segments

10 simple rules to create a serious game, illustrated with examples from structural biology

Serious scientific games are games whose purpose is not only fun. In the field of science, the serious goals include crucial activities for scientists: outreach, teaching and research. The number of serious games is increasing rapidly, in particular citizen science games, games that allow people to produce and/or analyze scientific data. Interestingly, it is possible to build a set of rules providing a guideline to create or improve serious games. We present arguments gathered from our own experience ( Phylo , DocMolecules , HiRE-RNA contest and Pangu) as well as examples from the growing literature on scientific serious games

From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules

Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted

Relation structure-fonction de protéines membranaires : de l'expérience à la modélisation et vice-versa

Mes recherches peuvent se caractériser par un travail centré sur des protéinesmembranaires et à l'interface modélisation/expérience construite au cours de monparcours.J'ai étudié pendant ma thèse des transferts d'électrons et de protons dans le centrephotosynthétique de Rhodobacter sphaeroides (bactérie pourpre) grace à des travauxexpérimentaux et de modélisation.J'ai effectué un premier post-doctorat à l’institut Pasteur. Mes travaux ont porté surl'étude de la structure et des transitions conformationnelles du récepteur nicotinique del’acétylcholine (nAChR). J’ai réalisé des travaux entièrement théoriques et en relationavec des travaux expérimentaux du laboratoire.Depuis mon intégration au CNRS j'ai initié un travail sur une autre famille derécepteur canaux (récepteur P2X de l'ATP) en étroite relation avec les expérimentateurs dulaboratoire d'accueil à Illkirch.Le passage par plusieurs laboratoire à notamment permis de créer un réseaux decollaborations solides avec des expérimentateurs ce qui me semble essentiel pour lapoursuite du projet

Is the Boundary of Fun Redefined in a Mixed-Reality Serious Game?

International audienceConsidering Games with the broad definition proposed by Juul (2010), consequences outside of the magic circle can be negotiated. This definition opens up the possibility to define serious games-games developed with a utilitarian goal in mind-in addition to fun. The entertaining and utilitarian objectives may however be contradictory, leading serious games to be, more often than not, less than optimal in at least one of the two dimensions. Another way to play with the boundaries of games is to consider pervasive games, which include alternate reality games, and cross-media games (Montola, 2005). We question here the limit between game, play and toy in the context of a mixed reality serious game. 'Pangu' is a game designed for undergraduate students, with biochemistry as the utilitarian objective, and the origin of life as a game theme. The students are asked to play the game on their smartphone, which in turn asks them to build molecules with a tangible balls-and-sticks model typically used in chemistry classes. Pictures taken from the models allow users to 'scan' these models and progress in the game. The use of the game was observed in four opportunities. An unanticipated observation is that, in addition to expected behaviours, some students briefly used the models like a toy rather than in the context of the game. It is therefore tempting to speculate that the pervasive nature of the game is blurring the game/non-game boundary and, in the context of this serious game, opens a door for fun. Some situations can be intuitively identified as play without any further analysis. Many situations are, however, more ambiguous and require a definition to be correctly characterized. Interestingly, these situations allow us to test our understanding (and associated definitions)

Normal mode analysis suggest a quaternary P.-J. Corringer et al

ABSTRACT We present a three-dimensional model of the homopentameric a7 nicotinic acetylcholine receptor (nAChR), that includes the extracellular and membrane domains, developed by comparative modeling on the basis of: 1), the x-ray crystal structure of the snail acetylcholine binding protein, an homolog of the extracellular domain of nAChRs; and 2), cryo-electron microscopy data of the membrane domain collected on Torpedo marmorata nAChRs. We performed normal mode analysis on the complete three-dimensional model to explore protein flexibility. Among the first 10 lowest frequency modes, only the first mode produces a structural reorganization compatible with channel gating: a wide opening of the channel pore caused by a concerted symmetrical quaternary twist motion of the protein with opposing rotations of the upper (extracellular) and lower (transmembrane) domains. Still, significant reorganizations are observed within each subunit, that involve their bending at the domain interface, an increase of angle between the two b-sheets composing the extracellular domain, the internal b-sheet being significantly correlated to the movement of the M2 a-helical segment. This global symmetrical twist motion of the pentameric protein complex, which resembles the opening transition of other multimeric ion channels, reasonably accounts for the available experimental data and thus likely describes the nAChR gating process