Interplay between the Ribosomal Tunnel,Nascent Chain,and Macrolides Influences Drug Inhibition

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Highlights? Macrolides exhibit nascent polypeptide chain–dependent inhibition ? Peptides can form specific interactions with the ribosomal tunnel ? A covalent bond between tylosin and the ribosome is necessary for inhibitory activity     

An N log N approximation based on the natural organization of biomolecules for speeding up the computation of long range interactions

Presented here is a method, the hierarchical charge partitioning (HCP) approximation, for speeding up computation of pairwise electrostatic interactions in biomolecular systems. The approximation is based on multiple levels of natural partitioning of biomolecular structures into a hierarchical set of its constituent structural components. The charge distribution in each component is systematically approximated by a small number of point charges, which, for the highest level component, are much fewer than the number of atoms in the component. For short distances from the point of interest, the HCP uses the full set of atomic charges available. For long‐distance interactions, the approximate charge distributions with smaller sets of charges are used instead. For a structure consisting of N charges, the computational cost of computing the pairwise interactions via the HCP scales as O(N log N), under assumptions about the structural organization of biomolecular structures generally consistent with reality. A proof‐of‐concept implementation of the HCP shows that for large structures it can lead to speed‐up factors of up to several orders of magnitude relative to the exact pairwise O(N²) all‐atom computation used as a reference. For structures with more than 2000–3000 atoms the relative accuracy of the HCP (relative root‐mean‐square force error per atom), approaches the accuracy of the particle mesh Ewald (PME) method with parameter settings typical for biomolecular simulations. When averaged over a set of 600 representative biomolecular structures, the relative accuracies of the two methods are roughly equal. The HCP is also significantly more accurate than the spherical cutoff method. The HCP has been implemented in the freely available nucleic acids builder (NAB) molecular dynamics (MD) package in Amber tools. A 10 ns simulation of a small protein indicates that the HCP based MD simulation is stable, and that it can be faster than the spherical cutoff method. A critical benefit of the HCP approximation is that it is algorithmically very simple, and unlike the PME, the HCP is straightforward to use with implicit solvent models. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

A molecular mechanics model for imatinib and imatinib:kinase binding

Imatinib is an important anticancer drug, which binds specifically to the Abl kinase and blocks its signalling activity. To model imatinib:protein interactions, we have developed a molecular mechanics force field for imatinib and four close analogues, which is consistent with the CHARMM force field for proteins and nucleic acids. Atomic charges and Lennard‐Jones parameters were derived from a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule interacting with imatinib fragments at 32 different positions. We considered both a neutral and a protonated imatinib. The final RMS deviation between the ab initio and force field energies, averaged over both forms, was 0.2 kcal/mol. The model also reproduces the ab initio geometry and flexibility of imatinib. To apply the force field to imatinib:Abl simulations, it is also necessary to determine the most likely imatinib protonation state when it binds to Abl. This was done using molecular dynamics free energy simulations, where imatinib is reversibly protonated during a series of MD simulations, both in solution and in complex with Abl. The simulations indicate that imatinib binds to Abl in its protonated, positively‐charged form. To help test the force field and the protonation prediction, we did MD free energy simulations that compare the Abl binding affinities of two imatinib analogs, obtaining good agreement with experiment. Finally, two new imatinib variants were considered, one of which is predicted to have improved Abl binding. This variant could be of interest as a potential drug. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Alteration of skin light-scattering and absorption properties by application of sunscreen nanoparticles: A Monte Carlo study

We report about the results of our investigations on the alteration of optical properties of the superficial layer of human skin at four UV range wavelengths, 310, 318, 360 and 400 nm, by application of 35-200 nm-sized particles of titanium dioxide (TiO₂), silicon (Si) and zinc oxide (ZnO). The theoretical study based on combination of the Mie theory and Monte Carlo simulations reveals the optimal sizes of the nanoparticles minimizing the light transmittance for the considered wavelengths.     

The analysis of the error statistics in a 5 × 40 Gbit/s fibre link with hybrid amplification

We quantify the error statistics and patterning effects in a 5 × 40 Gbit/s WDM RZ-OOK SMF/DCF fibre link using hybrid Raman/EDFA amplification. By extensive use of a numerical model, we determine how the error statistics change with the transmission distance. This knowledge is used as a basis for a constrained coding technique in order to improve the transmission error rate. We propose an adaptive constrained code for mitigation of the patterning effects and demonstrate that this approach can substantially reduce the bit error rate (BER) even for very large values of the channel BER (BER > 10^− 1). The proposed technique can be used in combination with forward error correction schemes (FEC) to extend the range of channel BERs that an FEC scheme is effective over.     

Observation of the chaotic spin-wave soliton trains in magnetic films

The transition from stationary to chaotic spin-wave soliton trains has been observed. The experiment utilized cw excitation of envelope solitons through self-modulation instability of spin waves. By increasing the spin-wave power, the secondary self-modulation instability succeeded the primary modulation instability, resulting in after-modulation of the soliton train amplitude. Further increase of the spin-wave power led to development of the higher-order instabilities, resulting in formation of the chaotic soliton train.     

Hot-electron-driven enhancement of spin-lattice coupling in Gd and Tb 4f ferromagnets observed by femtosecond x-ray magnetic circular dichroism

Femtosecond x-ray magnetic circular dichroism was used to study the time-dependent magnetic moment of 4f electrons in the ferromagnets Gd and Tb, which are known for their different spin-lattice coupling. We observe a two-step demagnetization with an ultrafast demagnetization time of 750 fs identical for both systems and slower times which differ sizeably with 40 ps for Gd and 8 ps for Tb. We conclude that spin-lattice coupling in the electronically excited state is enhanced up to 50 times compared to equilibrium.     

Towards Higgs boson production in gluon fusion to NNLO in the MSSM

We consider the Higgs boson production in the gluon-fusion channel to next-to-next-to-leading order within the Minimal Supersymmetric Standard Model. In particular, we present analytical results for the matching coefficient of the effective theory and study its influence on the total production cross section in the limit where the masses of all MSSM particles coincide. For supersymmetric masses below 500 GeV it is possible to find parameters leading to a significant enhancement of the Standard Model cross section, the K-factors, however, change only marginally.