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Inborn errors of metabolism (IEM) constitute a large class of genetic diseases, specific in that many of them are amenable to (nutritional) treatment, especially if detected early. As the first-line screening moves from metabolite to genetic, it opens new possibilities for the number of diseases that can be screened for, which in turn may bring them to the attention of the medical and nutrition industry - the existence of eff ective treatment currently being one of the prerequisites for the IEM to be included in the screening panel. Collecting data about the incidence of the IEM on the national level is a diffi cult process, and not systematically pursued. However, the information about human genetic variation is becoming available (e.g. ExAC database) on the scale that enables us to put a bracket on the expected incidence of all recognized IEMs with monogenic origin. We are collecting that information in a publicly available place (monogenic.org). In this presentation we discuss our current experience in using data integration - modeling of the related protein structure, evolutionary conservation, known disease causing variants, and the genetic variability in the protein coding regions of the genome, stratified across ethnic sub-populations - to put an upper limit on the expected incidence of IEMs. In 75% of the cases for which the information about the IEMs prevalence on the US national level we can make a reasonable prediction on its upper limit. The remaining cases, discussed here, bring to the attention the need to collect the information on a deeper genetic level, perhaps extend the defi nition of some diseases to include polygenic origin, and hopefully motivate the need for fur-ther systematic reporting on the IEMs detected through newborn screening.

RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins; however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma.

We have presented ExoLocator, an application for comparative analysis of exons (protein-coding regions of genes) found in vertebrate orthologs, as listed in the Ensembl repository. The main application of this type of analysis is in the interpretation of germline and somatic variants found in exons.

Hydrogen exchange mass spectrometry has the unique capability to record the footprint of protein-protein interaction using a comparatively small sample of purified protein. We have proposed a framework to increase the resolution and interpretability of the output of this type of experiment using molecular dynamics simulation.

We presented results from an interdisciplinary collaboration, combining protein crystallography and molecular dynamics simulation in understanding function and druggability of gelsolin, one of the key proteins involved in cell motility.

Background Computational comparison of two protein structures is the starting point of many methods that build on existing knowledge, such as structure modeling (including modeling of protein complexes and conformational changes), molecular replacement, or annotation by structural similarity. In a commonly used strategy, significant effort is invested in matching two sets of atoms. In a complementary approach, a global descriptor is assigned to the overall structure, thus losing track of the substructures within. Results Using a small set of geometric features, we define a reduced representation of protein structure, together with an optimizing function for matching two representations, to provide a pre-filtering stage in a database search. We show that, in a straightforward implementation, the representation performs well in terms of resolution in the space of protein structures, and its ability to make new predictions. Conclusions Perhaps unexpectedly, a substantial discriminating power already exists at the level of main features of protein structure, such as directions of secondary structural elements, possibly constrained by their sequential order. This can be used toward efficient comparison of protein (sub)structures, allowing for various degrees of conformational flexibility within the compared pair, which in turn can be used for modeling by homology of protein structure and dynamics.

We propose an algorithm for an efficient and scalable search through a database of protein structures that tolerates and encompasses differences related to protein structural flexibility.

Functional sites determine the activity and interactions of proteins and as such constitute the targets of most drugs. However, the exponential growth of sequence and structure data far exceeds the ability of experimental techniques to identify their locations and key amino acids. To fill this gap we developed a computational Evolutionary Trace method that ranks the evolutionary importance of amino acids in protein sequences. Studies show that the best-ranked residues form fewer and larger structural clusters than expected by chance and overlap with functional sites, but until now the significance of this overlap has remained qualitative. Here, we use 86 diverse protein structures, including 20 determined by the structural genomics initiative, to show that this overlap is a recurrent and statistically significant feature. An automated ET correctly identifies seven of ten functional sites by the least favorable statistical measure, and nine of ten by the most favorable one. These results quantitatively demonstrate that a large fraction of functional sites in the proteome may be accurately identified from sequence and structure. This should help focus structure–function studies, rational drug design, protein engineering, and functional annotation to the relevant regions of a protein.

We present results of a study of double layer quantum Hall systems in which each layer has a high-index Landau level that is half-filled. Hartree-Fock calculations indicate that, above a critical layer separation, the system becomes unstable to the formation of a unidirectional coherent charge density wave (UCCDW), which is related to stripe states in single layer systems(L. Brey and H.A. Fertig, Phys. Rev. B 62, 10268 (2000)). The UCCDW state supports low-energy modes associated with interlayer coherence, which for large enough separation and small tunneling amplitude have a line of nearly vanishing energy in the Brillouin zone. The system supports charged soliton excitations ; these become gapless in the limit of vanishing tunneling which should lead to power-law (i.e., critical) behavior in various correlation functions.

Using time-dependent Hartree-Fock approximation we study the excitations of a bilayer quantum Hall system with a half-filled high Landau level in each layer. For small separations the state is spatially uniform and the collective mode spectrum contains an isotropically, linearly dispersing Goldstone mode associated with interlayer coherence. Above a critical separation stripe ordering sets in, and a second Goldstone mode appears which dispersed quadratically as a function of k_allel for k_⊥=0. For increasing separation, the oscillator strength of the quadratic mode drops rapidly, and the linearly dispersing mode continuously evolves into a form similar to that of quantum Hall stripes in a single layer system. Possible consequences of this spectrum for fluctuation effects will be discussed.

We present results of investigation of structural and vibrational properties of intermediate size mixed clusters of silicon carbide, boron nitride and silicon-germanium using generalized tight-binding molecular dynamics simulation method of Menon and Subbaswamy and ab initio calculations. In particular, we obtain optimized geometries of hetero-fullerenes and compare our results with recent experiments on these systems. We propose pathways towards polymerization of fullerenes that will be more stable than the polymers formed with only carbon fullerenes.

Motivated by the recent evidence for existence of small sized spin structured excitations in higher Landau levels footnote Song et al., PRL 82, 2768, 1999 we investigate the influence of Landau level mixing, screening by filled Landau levels, and finite well thickness, on the size and stability of these "Skyrmionic" excitations. Our approach is a real-space Hartree-Fock approximation. The computational results will be compared with the available experimental data.

Electron systems confined to a plane in a perpendicular magnetic field exhibit many interesting and unusual properties. This was a subject of voluminous research in the past twenty years. The phenomena occurring in this regime can be roughly classified according to the filling factor: the ratio of number of electrons in the system and the total magnetic flux measured in units of magnetic flux quanta. The focus here is on two problems: the behavior of low lying excitations of the system with spin (skyrmions) in the weak magnetic field close to the filling factor of one, and collective excitations of unidirectional charge density wave phase in the double well system, appearing at the filling factor of one half. The principal methods of investigation are the Hartree-Fock and the time dependent Hartree-Fock method. The key results are the phase diagram of the skyrmion stability as a function of magnetic field strength and tilt and dispersion relations for double well coherent unidirectional charge density wave.

The phase diagram of a 2D crystal in the presence of a quenched, slowly varying random potential is investigated. An effective Hamiltonian for dislocations in the presence of disorder footnote M.C. Cha and H.A. Fertig, PRL 74, 4867 (1995). [T. Natterman, S. Scheidl, and M.S. Li, J. de Physique 5, 565 (1995).] is simulated using Monte-Carlo methods, and the melting transition is characterized (as in the absence of disorder) by the unbinding of dislocation pairs. The transition temperature between crystal and hexatic states for different disorder strengths is located by tracking the size behavior of the effective coupling constant between dislocations [M. Rubinstein, B. Shraiman, and D.R. Nelson, PRB 27), 1800 (1983)]. It is found that the crystal phase is stable at low temperatures for sufficiently weak (but non-vanishing) disorder, and approximately follows the behavior proposed in Refs. 3 and 4.

Provedeni su kompjutorski racuni niskoležećih stanja u jezgri 129I, koristeći IBFM model ranije razvijen u Zagrebu, u usporedbi s novim eksperimentalnim rezultatima dobivenim u nizu svjetskih laboratorija.