We describe a framework that combines ensemble MD simulations and virtual reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes.
J. Juárez-Jiménez, P. Tew, M. O′Connor, S. Llabrés, R. Sage, D. Glowacki, J. Michel
Proteins need to interconvert between many conformations in order to function, many of which are formed transiently and are extremely difficult to characterize. We introduce a novel combination of accelerated MD (aMD) simulations and Markov state modelling (MSM) to explore these ‘excited’ conformational states.
J. Juárez-Jiménez, A.A. Gupta, G. Karunanithy, A.S.J.S Mey, C. Georgiou, H. Ioannidis, A. De Simone, P. N. Barlow, A.N. Hulme, M.D. Walkinshaw, A.J. Baldwin, J. Michel
We nvestigated the binding of amantadine (Amt) to the wild type (wt) M2 channel and its V27A variant using multiple enhanced sampling techniques. The results allow us to propose a sequential mechanism for the (un)binding of Amt to the wt M2 channel, which involves the adoption of a transiently populated intermediate (up state) leading to the thermodynamically favored down binding mode in the channel pore. Furthermore a pseudoirreversible, kinetically driven binding mechanism is proposed as supported by modelling and experimental evidence.
S. Llabrés, J. Juárez-Jiménez, M. Masetti, R. Leiva, S. Vázquez, S. Gazzarrini, A. Moroni, A. Cavalli, F.J. Luque (*Shared first authorship)
In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution.
J. Juárez-Jiménez, X. Barril, M. Orozco, R. Pouplana, F.J. Luque
We have synthesized, tested and modelled a family of rhein–huprine hybrids to hit several key targets for Alzheimer’s disease.
E. Viayna, I. Sola, M. Bartolini, A. De Simone, C. Tapia-Rojas, F.G. Serrano, R. Sabaté Lagunas, J. Juárez-Jiménez, B. Pérez Fernández, F.J. Luque, V. Andrisano, M. Clos, N.C. Inestrosa, D. Muñoz-Torrero
A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B was synthesized, tested and modelled. The results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer’s disease therapy.
I. Bolea, J. Juárez-Jiménez, C. de los Rı́os, M. Chioua, R. Pouplana, F.J. Luque, M. Unzeta, J. Marco-Contelles, A. Samadi (*Shared first authorship)