Abstract
Fluorescent probes have been employed for more than half a century to study the structure and dynamics of model and biological membranes, using spectroscopic and/or microscopic experimental approaches. While their utilization has led to tremendous progress in our knowledge of membrane biophysics and physiology, in some respects the behavior of bilayer-inserted membrane probes has long remained inscrutable. The location, orientation and interaction of fluorophores with lipid and/or water molecules are often not well known, and they are crucial for understanding what the probe is actually reporting. Moreover, because the probe is an extraneous inclusion, it may perturb the properties of the host membrane system, altering the very properties it is supposed to measure. For these reasons, the need for independent methodologies to assess the behavior of bilayer-inserted fluorescence probes has been recognized for a long time. Because of recent improvements in computational tools, molecular dynamics (MD) simulations have become a popular means of obtaining this important information. The present review addresses MD studies of all major classes of fluorescent membrane probes, focusing in the period between 2011 and 2020, during which such work has undergone a dramatic surge in both the number of studies and the variety of probes and properties accessed.
Highlights
Fluorescent molecules have been very important tools in the characterization of biomembrane properties since the late 1960s [1,2,3,4,5]
This study shows that experimental studies using common membrane probes may be interpreted incorrectly, and that molecular dynamics (MD) simulations may help understanding what is happening in such cases
The direct comparison between the C6 NBD-PC and C12 NBD-PC (Figure 3d) probes, which reside in the same location of the PC bilayers, shows that different tilt angles of the NBD fluorophore correlate with higher exposure of the nitro group to the water phase and higher degree of quenching
Summary
Fluorescent molecules have been very important tools in the characterization of biomembrane properties since the late 1960s [1,2,3,4,5]. Atom charges could still be obtained from quantum calculations carried out outside these tools, following the recipes provided in the original force field development papers The availability of these parameterization tools, combined with the interest in understanding both the behavior of probes and the effects induced on host membrane properties, has predictably led to a marked increase in the number of computational studies of fluorescence membrane probes, as well as a diversification of the chemical structures of the studied compounds. There has been a surge in studies where biased simulations with enhanced sampling are used to obtain equilibrium and kinetic properties related to the interaction of small molecules (namely drugs) with the bilayers Those studies provide directly the energy profile for the solute in the aqueous media and at different depths in the membrane, from which the rate of translocation and overall permeation may in principle be calculated [23,24,25]. It must be emphasized that correct parametrization, simulation and analysis protocols are absolutely crucial for the obtainment of meaningful information, and we duly comment below some instances where we found them visibly questionable
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