Conformation and dynamics of human urotensin II and urotensin related peptide in aqueous solution

Conformation and dynamics of the vasoconstrictive peptides human urotensin II (UII) and urotensin related peptide (URP) have been investigated by both unrestrained and enhanced-sampling molecular-dynamics (MD) simulations and NMR spectroscopy. These peptides are natural ligands of the G-protein coupled urotensin II receptor (UTR) and have been linked to mammalian pathophysiology. UII and URP cannot be characterized by a single structure but exist as an equilibrium of two main classes of ring conformations, <i>open</i> and <i>folded</i>, with rapidly interchanging subtypes. The <i>open</i> states are characterized by turns of various types centered at K⁸Y⁹ or F⁶W⁷ predominantly with no or only sparsely populated transannular hydrogen bonds. The <i>folded</i> conformations show multiple turns stabilized by highly populated transannular hydrogen bonds comprising centers F⁶W⁷K⁸ or W⁷K⁸Y⁹. Some of these conformations have not been characterized previously. The equilibrium populations that are experimentally difficult to access were estimated by replica-exchange MD simulations and validated by comparison of experimental NMR data with chemical shifts calculated with density-functional theory. UII exhibits approximately 72% <i>open</i>:28% <i>folded</i> conformations in aqueous solution. URP shows very similar ring conformations as UII but differs in an <i>open:folded</i> equilibrium shifted further toward <i>open</i> conformations (86:14) possibly arising from the absence of folded N-terminal tail-ring interaction. The results suggest that the different biological effects of UII and URP are not caused by differences in ring conformations but rather by different interactions with UTR

Uzroci i prevencija ispadanja mladih iz sustava obrazovanja

Socijalni rad je djelatnost koja je nastala na humanitarnim i demokratskim idealima te su njegove vrijednosti temeljene na poštivanju jednakosti i dostojanstvu svih ljudi. Svrha socijalnog rada je promoviranje i očuvanje uzajamne dobrobiti između pojedinca i društva kako bi se unaprijedila kvaliteta njihova života. U obrazovnom sustavu je presudna uloga socijalnih radnika jer oni prate i ocjenjuju stanje učenika u svrhu poboljšanja njihova života u obitelji, zajednici i školi, ali i sprječavanju ranog napuštanja školovanja. Obrazovanje je osnovno ljudsko pravo, ali sve češće su vidljivi problemi i propusti obrazovnih sustava koji ugrožavaju budućnost djece svojim lošim provođenjem i implementacijom. Razlozi ispadanja mladih iz sustava obrazovanja su različiti, a najčešći su oni koji su povezani sa obiteljskom i školskom sredinom. Ispadanje iz sustava obrazovanja negativno utječe na pojedinca i na cjelokupnu društvenu zajednicu. Od presudne je važnosti je suradnja škole i ostalih organizacija kako bi se spriječilo rano napuštanje škole, kroz edukacijske programe te individualni rad s učenicima i njihovim roditeljima.Social work is an industry which was created on humanitarian and democratic ideals and its values are founded on the respect of equality and dignity of all people. The purpose of social work is to promote and preserve corelative well-being between the individuals and the community to benefit their life quality. The role of social workers in the education system is crucial wherefore they observe and assess the state of students to benefit their life at home, in the community and at school with the goal to prevent early school leaving. Education is the fundamental human right, but the problems and flaws of the education systems are frequent witch are risking the future of children thru bad performance and implementation. The causes of early school leaving are different, but the most common ones are related with family and school environment. Early school leaving has negative effects on the individual and on the whole social community. The collaboration between schools and other organizations are crucial to prevent early school leaving via education programmes and individual work with students and their parents

Uzroci i prevencija ispadanja mladih iz sustava obrazovanja

Socijalni rad je djelatnost koja je nastala na humanitarnim i demokratskim idealima te su njegove vrijednosti temeljene na poštivanju jednakosti i dostojanstvu svih ljudi. Svrha socijalnog rada je promoviranje i očuvanje uzajamne dobrobiti između pojedinca i društva kako bi se unaprijedila kvaliteta njihova života. U obrazovnom sustavu je presudna uloga socijalnih radnika jer oni prate i ocjenjuju stanje učenika u svrhu poboljšanja njihova života u obitelji, zajednici i školi, ali i sprječavanju ranog napuštanja školovanja. Obrazovanje je osnovno ljudsko pravo, ali sve češće su vidljivi problemi i propusti obrazovnih sustava koji ugrožavaju budućnost djece svojim lošim provođenjem i implementacijom. Razlozi ispadanja mladih iz sustava obrazovanja su različiti, a najčešći su oni koji su povezani sa obiteljskom i školskom sredinom. Ispadanje iz sustava obrazovanja negativno utječe na pojedinca i na cjelokupnu društvenu zajednicu. Od presudne je važnosti je suradnja škole i ostalih organizacija kako bi se spriječilo rano napuštanje škole, kroz edukacijske programe te individualni rad s učenicima i njihovim roditeljima.Social work is an industry which was created on humanitarian and democratic ideals and its values are founded on the respect of equality and dignity of all people. The purpose of social work is to promote and preserve corelative well-being between the individuals and the community to benefit their life quality. The role of social workers in the education system is crucial wherefore they observe and assess the state of students to benefit their life at home, in the community and at school with the goal to prevent early school leaving. Education is the fundamental human right, but the problems and flaws of the education systems are frequent witch are risking the future of children thru bad performance and implementation. The causes of early school leaving are different, but the most common ones are related with family and school environment. Early school leaving has negative effects on the individual and on the whole social community. The collaboration between schools and other organizations are crucial to prevent early school leaving via education programmes and individual work with students and their parents

Conformational sampling of intrinsically disordered peptides by enhanced sampling methods

The aim of this study was to explore the conformational equilibrium of four cyclic hormone peptides in order to investigate to what extent the bound conformational state can be observed from the solution phase simulations. The studied cyclic peptides share the same structural motif of a six membered ring closed by disulphide bridge between the cysteine residues. They also belong to the class of intrinsically disordered peptides known to exist in an equilibrium of different conformations. Elucidating their conformational ensemble using traditional experimental techniques has proven hard due to the fast interconversion between conformational states, and thus molecular dynamics simulation may help in providing a detailed picture of the peptide’s conformational ensemble.However, conventional molecular dynamics simulation are limited by the long time scale required to observe many conformational motions. Therefore in this work Replica Exchange techniques were applied to test the rate of convergence in conformational sampling. Moreover, to predict the conformational equilibrium of the peptides, a combination of results from enhanced sampling methods, DFT calculations and NMR experiments was used. It was found that calculated chemical shifts weighted by the ensemble populations of each conformational state were better able to reproduce the experimental chemical shift data, over and above any single peptide conformation. This result supports the use of enhanced sampling molecular dynamics computer simulations to study intrinsically disordered peptides.The knowledge of the conformational equilibrium and the relative populations of the unbound states of the peptides obtained using this approach may help in predicting the structural and functional roles of the bound state peptide. Another purpose of this work was also to check the extent to which a difference in peptide sequence may contribute to their functional diversity. Finally, the performance of the Replica Exchange simulations was compared, indicating that Solute Tempering is to be preferred over temperature Replica Exchange for reasons of computational efficiency

Uzroci i prevencija ispadanja mladih iz sustava obrazovanja

Socijalni rad je djelatnost koja je nastala na humanitarnim i demokratskim idealima te su njegove vrijednosti temeljene na poštivanju jednakosti i dostojanstvu svih ljudi. Svrha socijalnog rada je promoviranje i očuvanje uzajamne dobrobiti između pojedinca i društva kako bi se unaprijedila kvaliteta njihova života. U obrazovnom sustavu je presudna uloga socijalnih radnika jer oni prate i ocjenjuju stanje učenika u svrhu poboljšanja njihova života u obitelji, zajednici i školi, ali i sprječavanju ranog napuštanja školovanja. Obrazovanje je osnovno ljudsko pravo, ali sve češće su vidljivi problemi i propusti obrazovnih sustava koji ugrožavaju budućnost djece svojim lošim provođenjem i implementacijom. Razlozi ispadanja mladih iz sustava obrazovanja su različiti, a najčešći su oni koji su povezani sa obiteljskom i školskom sredinom. Ispadanje iz sustava obrazovanja negativno utječe na pojedinca i na cjelokupnu društvenu zajednicu. Od presudne je važnosti je suradnja škole i ostalih organizacija kako bi se spriječilo rano napuštanje škole, kroz edukacijske programe te individualni rad s učenicima i njihovim roditeljima.Social work is an industry which was created on humanitarian and democratic ideals and its values are founded on the respect of equality and dignity of all people. The purpose of social work is to promote and preserve corelative well-being between the individuals and the community to benefit their life quality. The role of social workers in the education system is crucial wherefore they observe and assess the state of students to benefit their life at home, in the community and at school with the goal to prevent early school leaving. Education is the fundamental human right, but the problems and flaws of the education systems are frequent witch are risking the future of children thru bad performance and implementation. The causes of early school leaving are different, but the most common ones are related with family and school environment. Early school leaving has negative effects on the individual and on the whole social community. The collaboration between schools and other organizations are crucial to prevent early school leaving via education programmes and individual work with students and their parents

How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP, TP2 and ONEG?

Understanding the conformational ensembles of intrinsically disordered proteins and peptides (IDPs) in their various biological environments is essential for understanding their mechanisms and functional roles in the proteome, leading to a greater knowledge of, and potential treatments for, a broad range of diseases. To determine whether molecular simulation is able to generate accurate conformational ensembles of IDPs, we explore the structural landscape of the PLP peptide (an intrinsically disordered region of the proteolipid membrane protein) in aqueous and membrane-mimicking solvents, using replica exchange with solute scaling (REST2), and examine the ability of four force fields (ff14SB, ff14IDPSFF, CHARMM36 and CHARMM36m) to reproduce literature circular dichroism (CD) data. Results from variable temperature (VT) 1H and Rotating frame Overhauser Effect SpectroscopY (ROESY) nuclear magnetic resonance (NMR) experiments are also presented and are consistent with the structural observations obtained from the simulations and CD. We also apply the optimum simulation protocol to TP2 and ONEG (a cell-penetrating peptide (CPP) and a negative control peptide, respectively) to gain insight into the structural differences that may account for the observed difference in their membrane-penetrating abilities. Of the tested force fields, we find that CHARMM36 and CHARMM36m are best suited to the study of IDPs, and accurately predict a disordered to helical conformational transition of the PLP peptide accompanying the change from aqueous to membrane-mimicking solvents. We also identify an α-helical structure of TP2 in the membrane-mimicking solvents and provide a discussion of the mechanistic implications of this observation with reference to the previous literature on the peptide. From these results, we recommend the use of CHARMM36m with the REST2 protocol for the study of environment-specific IDP conformations. We believe that the simulation protocol will allow the study of a broad range of IDPs that undergo conformational transitions in different biological environments.</p

Conformation and dynamics of human urotensin II and urotensin related peptide in aqueous solution

Conformation and dynamics of the vasoconstrictive peptides human urotensin II (UII) and urotensin related peptide (URP) have been investigated by both unrestrained and enhanced-sampling molecular-dynamics (MD) simulations and NMR spectroscopy. These peptides are natural ligands of the G-protein coupled urotensin II receptor (UTR) and have been linked to mammalian pathophysiology. UII and URP cannot be characterized by a single structure but exist as an equilibrium of two main classes of ring conformations, open and folded, with rapidly interchanging subtypes . The open states are characterized by turns of various types centered at K8Y9 or F6W7 predominantly with no or only sparsely populated transannular hydrogen bonds. The folded conformations show multiple turns stabilized by highly populated transannular hydrogen bonds comprising centers F6W7K8 or W7K8Y9. Some of these conformations have not been characterized previously. The equilibrium populations that are experimentally difficult to access were estimated by replica-exchange MD simulations and validated by comparison of experimental NMR data with chemical shifts calculated with density-functional theory. UII exhibits approximately 72% open : 28% folded conformations in aqueous solution. URP shows very similar ring conformations as UII but differs in an open:folded equilibrium shifted further toward open conformations (86:14) possibly arising from the absence of folded N-terminal tail - ring interaction. The results suggest that the different biological effects of UII and URP are not caused by differences in ring conformations but rather by different interactions with UTR