Mechanism of stabilization of helix secondary structure by constrained Cα-tetrasubstituted alpha-amino acids

The theoretical basis behind the ability of constrained C\u3b1-tetrasubstituted amino acids (CTAAs) to induce stable helical conformations has been studied through Replica Exchange Molecular Dynamics Potential of Mean Force Quantum Theory of Atoms In Molecules calculations on Ac-l-Ala-CTAA-l-Ala-Aib-l-Ala-NHMe peptide models. We found that the origin of helix stabilization by CTAAs can be ascribed to at least two complementary mechanisms limiting the backbone conformational freedom: steric hindrance predominantly in the (+x,+y,\u2013z) sector of a right-handed 3D Cartesian space, where the z axis coincides with the helical axis and the C\u3b1 of the CTAA lies on the +y axis (0,+y,0), and the establishment of additional and relatively strong C\u2013H\ub7\ub7\ub7O interactions involving the CTAA

Efficient time-domain simulation of lossy multiconductor transmission lines by means of generalized method of characteristics

Abstract The paper investigates some crucial aspects in the derivation of time-domain equivalent circuits of lossy multiconductor transmission lines, obtained by using the generalized method of characteristic. The paper highlights how an exact evaluation of the effect of the propagation delays not only provide an accurate time-domain equivalent circuit, but suggests naturally the way to obtain a reduced-order model. The propagation is described correctly by means of damped delayed sources, while the effects of losses are efficiently taken into account by a low-order approximated lumped circuit. In this way it is easy to circumvent the main problems arising when using the generalized method of characteristic that is the correct evaluation of the impulse responses describing the time-domain model and the computational cost of the time-domain convolutions

Cerebellum in timing control: Evidence from contingent negative variation after cerebellar tDCS

Background and aims Timing control is defined as the ability to quantify time. The temporal estimation of supra-seconds range is generally seen as a conscious cognitive process, while the sub-seconds range is a more automatic cognitive process. It is accepted that cerebellum contributes to temporal processing, but its function is still debated. The aim of this research was to better explore the role of cerebellum in timing control. We transitorily inhibited cerebellar activity and studied the effects on CNV components in healthy subjects. Methods Sixteen healthy subjects underwent a S1-S2 duration discrimination motor task, prior and after cathodal and sham cerebellar tDCS, in two separate sessions. In S1-S2 task they had to judge whether the duration of a probe interval trial was shorter (Short-ISI-trial:800 ms), longer (long-ISI-trail:1600 ms), or equal to the Target interval of 1200 ms. For each interval trial for both tDCS sessions, we measured: total and W2-CNV areas, the RTs of correct responses and the absolute number of errors prior and after tDCS. Results After cathodal tDCS a significant reduction in total-CNV and W2-CNV amplitudes selectively emerged for Short (p < 0.001; p = 0.003 respectively) and Target-ISI-trial (total-CNV: p < 0.001; W2-CNV:p = 0.003); similarly, a significant higher number of errors emerged for Short (p = 0.004) and Target-ISI-trial (p = 0.07) alone. No differences were detected for Longer-ISI-trials and after sham stimulation. Conclusions These data indicate that cerebellar inhibition selectively altered the ability to make time estimations for second and sub-second intervals. We speculate that cerebellum regulates the attentional mechanisms of automatic timing control by making predictions of interval timing

Mental flexibility in Parkinson's disease with central fatigue: Data from the frontal assessment battery

Background and aims Central fatigue is defined as a reduced energy level or an increased perception of effort, often associated to a failure in initiating and maintaining tasks that require self-motivation. It is common in Parkinson's disease population and it has been hypothesized to be related to a dysfunction in the striato-talamo- prefrontal loop. The aim of the present study was to explore the association between fatigue and executive functions as index of integrity of the striato-thalamo-prefrontal loop. Methods Twenty-nine non-demented PD patients without fatigue - PDnF, 28 non-demented PD patients with fatigue - PDF and 26 age and sex- matched controls underwent an evaluation with the Frontal Assessment Battery (FAB), MMSE, PSQI, BDI, STAI Y1-2, PDQ-39. Differences between groups in FAB scores (total and subitems) were analyzed by means of Kruskal-Wallis test. Moreover, a correlation between fatigue and FAB was also analyzed. Results Overall parkinsonian population displayed worse performance than controls in frontal scores especially inhibitory control (p = 0.008) and sensitivity to interference (p = 0.014). PDF displayed significantly worse than PDnF in verbal fluency (p = 0.05). Fatigue severity inversely correlated with executive performance (p b 0.001). Conclusions Phonemic fluency tasks are thought to reflect the simultaneous engagement of several executive functions such as attention, working memory, retrieval, information processing. The association of central fatigue with a deficit in mental flexibility, could support the hypothesis that central fatigue is a reliable index of the impairment of higher executive functions needed in order to effectively assess costs and benefits related to adaptive decision- making behavior

Advances in the treatment of explicit water molecules in docking and binding free energy calculations

BACKGROUND: The inclusion of direct effects mediated by water during the ligand-receptor recognition is a hot-topic of modern computational chemistry applied to drug discovery and development. Docking or virtual screening with explicit hydration is still debatable, despite the successful cases that have been presented in the last years. Indeed, how to select the water molecules that will be included in the docking process or how the included waters should be treated remain open questions. OBJECTIVE: In this review, we will discuss some of the most recent methods that can be used in computational drug discovery and drug development when the effect of a single water, or of a small network of interacting waters, needs to be explicitly considered. RESULTS: Here, we analyse software to aid the selection, or to predict the position, of water molecules that are going to be explicitly considered in later docking studies. We also present software and protocols able to efficiently treat flexible water molecules during docking, including examples of applications. Finally, we discuss methods based on molecular dynamics simulations that can be used to integrate docking studies or to reliably and efficiently compute binding energies of ligands in presence of interfacial or bridging water molecules. CONCLUSIONS: Software applications aiding the design of new drugs that exploit water molecules, either as displaceable residues or as bridges to the receptor, are constantly being developed. Although further validation is needed, workflows that explicitly consider water will probably become a standard for computational drug discovery soon