885 research outputs found
A semiautomated Nwat-MM-GBSA workflow for fast and accurate predictions of relative binding free energies
No full textDespite the development of high-throughput computational methods able to screen very large libraries in a short time, the reliable prediction of binding free energy can still be important in drug design.1,2 Although quite computationally expensive, molecular dynamics (MD), providing a statistically meaningful conformational ensemble for thermodynamic calculations, are within the most accurate tecqniques to predict interaction free energies of biomolecules. Among MD-based methods, one of the most popular is Molecular Mechanics Poisson−Boltzmann/Generalized Born Surface Area (MM-PB/GBSA).3
We recently reported on how the inclusion of a certain number of explicit waters (Nwat), chosen to be the closest to the ligand atoms, can improve the correlation between MM-PB and GBSA computed binding energy and experimental activities (Fig. 1).4
Fig. : Effect of the inclusion of explicit waters in the correlation of computed and experimental activities for a set of topoisomerase inhibitors
Here, we will present a semiautomated workflow to compute MM-GBSA relative binding energies starting from a set of complexes, either obtained through X-ray crystallography, homology modelling or docking simulations, by taking advantage of GPU calculations and with a minimal effort by the user.
We will also discuss specific examples of application on protein-ligand and protein-protein complexes.
REFERENCES
1. Durrant, J.D.; McCammon, J.A. Molecular dynamics simulations and drug discovery. BMC Biology 2011, 9:71
2. Zhao, H.; Caflish, A. Molecular dynamics in drug design. Eur. J. Med. Chem. 2014, doi:10.1016/j.ejmech.2014.08.004
3. Massova, I.; Kollman, P. Combined molecular mechanical and continuum solvent approach (MM-PBSA/GBSA) to predict ligand binding. Perspect. Drug Discov. 2000, 18 (1), 113-135
4. Maffucci, I.; Contini, A. Explicit Ligand Hydration Shells Improve the Correlation between
MM-PB/GBSA Binding Energies and Experimental Activities J. Chem. Theory Comput. 2013, 9, 2706-2717
Improving the reliability of MM-PBSA and MM-GBSA binding energy predictions by explicitly considering ligand solvation shells
No full textMolecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) are interesting techniques for drug design/discovery applications, but sometimes the correlation between predicted and experimental binding energies might result unsatisfactory.
Nowadays, a certain effort is focused on ameliorating the solvation term in MM-PB/GBSA calculations and some strategies were applied to obtain a better correlation between calculations and experiments.
Some authors reported that the predictivity of MM-PB/GBSA calculations might be improved by modulating the internal dielectric constant (εin).1 Unfortunately, a universal εin, suitable for all systems was not found and a thorough analysis of the binding pocket is needed to choose the proper value of εin.
MM-PB/GBSA binding energy predictions might also be improved by explicitly considering selected water molecules in the calculation, however this strategy is controversial.2-5
Herein, we report on how the explicit inclusion of variably populated ligand hydration shells might improve the correlation between MM-PB/GBSA computed binding energy and experimental activities.
DNA-topoisomerase, α-thrombin, penicillopepsin, avidin, and neuraminidase complexes with different ligands were considered as test sets, and ligand hydration shells populated by an increasing number of water molecules were systematically evaluated.
We found that the consideration of a hydration shell populated by a number of water residues (Nwat) between 30 and 70 provided in all the considered examples a positive effect on correlation between MM-PB/GBSA calculated binding affinities and experimental activities, with a negligible increment of computational cost.6
REFERENCES
1. Hou, T.; Wang, J.; Li, Y.; Wang, W., J. Chem. Inf. Model. 2011, 51, 69-82.
2. Wong, S.; Amaro, R. E.; McCammon, J. A., J. Chem. Theory Comput. 2009, 5, 422-429.
3. Hayes, J. M.; Skamnaki, V. T.; Archontis, G.; Lamprakis, C.; Sarrou, J.; Bischler, N.; Skaltsounis, A.-L.; Zographos, S. E.; Oikonomakos, N. G., Proteins 2011, 79, 703-19.
4. Freedman, H.; Huynh, L. P.; Le, L.; Cheatham, I. I. I. T. E.; Tuszynski, J. A.; Truong, T. N., J. Phys. Chem. B 2010, 114, 2227-2237.
5. Checa, A.; Ortiz, A. R.; de Pascual-Teresa, B.; Gago, F., J. Med. Chem. 1997, 40 (25), 4136-45.
6. Maffucci, I.; Contini, A., J. Chem. Theory Comput. 2013, 9 (6), 2706-2717
A case of Maffucci syndrome
No full textThe Maffucci syndrome consists of a combination of multiple enchondromas and haemangiomas. It appears in the first two decades of life, with no family history. In this case we are reporting about a 26-year-old female who had suffered from multiple enchondromas since the age of two. At the age of nine, the patient presented with additional haemangiomas, which facilitated making proper diagnosis. She now presents with a massive lesion of her left upper extremity. The patient had initially rejected operative treatment when the disease was at early stages. At later stages, a more complex reconstruction of the hand would have been necessary to secure hand function. This procedure that sometimes induces a risk related to potential necessity of blood transfusion was rejected by the patient for religious reasons. Amputation of the extremity was therefore the last resort procedure
Class II Phosphoinositide 3-Kinases Contribute to Endothelial Cells Morphogenesis
No full textPMCID: PMC3539993This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
On the dynamic equations of linear multiconductor transmission lines with terminal nonlinear multiport resistors
No full textDistributed circuits composed of linear multiconductor transmission lines and terminated with nonlinear weakly active multiport resistors are considered. The line is represented as a linear dynamic multiport through recursive convolution relations and special considerations are given to some general properties of the line impulse responses. The convolution technique allows the mathematical description of these distributed circuits by means of a sea: of nonlinear algebraic-integral equations of Volterra type for the terminal voltages and currents. The conditions under which these governing equations can he reformulated as a set of Volterra integral equations of second kind in normal form are given with the explicit means for doing so. These conditions also assure the existence and the uniqueness of the solution. In particular if the terminal multiport resistors are strictly locally passive, then the normal form exists and the solution is unique. Transmission lines with terminal multiport resistors that are locally active may not admit a normal form for the governing equations, and hence, several solutions that have the same initial conditions are possible, In these cases a simple method is presented for revising the original network model so that the normal form exists, and hence, the uniqueness of solution is assured, under mild restrictions
Irregular Terms in the Impulse Response of a Multiconductor Lossy Transmission Line
No full textLinear multiconductor transmission lints can be effectively represented in the time domain as a dynamic multiport through the describing input and transfer impulse responses, Unfortunately, these responses cannot be analytically evaluated for the most general case of lossy lines. In addition, they cannot even be evaluated numerically due to the presence of irregular terms such as Dirac pulses, functions that actually approximates Dirac pulses, and functions of the type 1/root t. Nevertheless, all these irregular terms can be isolated from the regular ones. This paper proposes an analytical method to evaluate exactly the irregular terms. This method is based on the perturbation theory of the spectrum of symmetric matrices and can be easily and effectively applied to the most general case of frequency-dependent lossy multiconductor lines. Once the irregular parts of the impulse responses are known, it is possible to evaluate accurately the regular ones through simple numerical methods, as shown through some examples
IDENTIFICATION OF A SPICE REDUCED-ORDER MODEL FOR LOSSY INTERCONNECTS FROM TERMINAL BEHAVIOR
No full textAngelo Maffucci
No full textBiografia del medico Angelo Maffucci. Dopo aver partecipato alla campagna sanitaria contro il colera nel napoletano, divenne medico vaccinatore per il Comune di Napoli e chirurgo presso l'Ospedale degli incurabili nella stessa città. Insegnò anatomia patologica prima a Catania, dove diresse l'Istituto di anatomia patologica, poi a Pisa, dove fu anche preside della Facoltà di medicina e primario dell'Ospedale, fondando anche un gabinetto di istochimica. I suoi studi si focalizzarono sulle patologie epatiche, infettive e su alcuni tipi di tumori, in particolare individuò una entità anatomoclinica che si caratterizza per l’associazione di un tumore cartilagineo benigno e di angiomi cutanei, nota con il nome di “sindrome di Maffucci
Maffucci′s syndrome associated with hyperparathyroidism
No full textMaffucci′s syndrome is a rare, congenital, nonhereditary, mesodermal dysplastic disease characterized by venous malformations and benign cartilaginous tumors. The occurrence of endocrine tumors in Maffucci′s syndrome is very rare. We report a case of Maffucci′s syndrome associated with hyperparathyroidism and multinodular goiter
TIME-DOMAIN TWO-PORT REPRESENTATION OF SOME NONUNIFORM TWO-CONDUCTOR TRANSMISSION LINES
No full textThis brief proposes a new procedure to extend to nonuniform transmission lines, a time-domain model commonly used to describe uniform transmission lines. The line is represented at its terminations as a dynamic two-port, where each port is composed by a dynamic one-port connected in series with a controlled voltage source. The procedure is applied to nonuniform lines with exponential, linear and Gaussian profile of the parameters. The numerical analysis of some case-studies is carried out
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