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The sensing response of 15-crown-5-ether functionalized polythiophene to Li+, Na+, and K+ has been investigated at the atomistic level using molecular dynamics simulations. The stability associated with all the identified binding sites has been corroborated by quantum mechanical calculations. Although the cavity of the macrocycle is not the most visited binding site, such receptor is responsible of the selective sensing response of this polythiophene derivative. PF6– counterions reduce the mobility of the alkaline cations, which do not occupy the crown ether cavity of consecutive repeating units due to electrostatic repulsions. Furthermore, the relative entropy for the “free state → bound state” has been estimated using a procedure based on the covariance matrix atom-positional fluctuations. Evaluation of the entropic contributions allow us to complete the thermodynamics scenario of binding process, which was recently initiated by calculating the enthalpies at quantum mechanical level [ Chem. Eur. J. 2009, 15, 4676]. Results indicate an entropycally driven binding preference.

The prediction capabilities of atomistic simulations of peptides are hampered by different difficulties, including the reliability of force fields, the treatment of the solvent or the adequate sampling of the conformational space. In this work, we have studied the conformational profile of the 10 residue miniprotein CLN025 known to exhibit a β-hairpin in its native state to understand the limitations of implicit methods to describe solvent effects and how these may be compensated by using different force fields. For this purpose, we carried out a thorough sampling of the conformational space of CLN025 in explicit solvent using the replica exchange molecular dynamics method as a sampling technique and compared the results with simulations of the system modeled using the analytical linearized Poisson-Boltzmann (ALPB) method with three different AMBER force fields: parm94, parm96, and parm99SB. The results show the peptide to exhibit a funnel-like free energy landscape with two minima in explicit solvent. In contrast, the higher minimum nearly disappears from the energy surface when the system is studied with an implicit representation of the solvent. Moreover, the different force fields used in combination with the ALPB method do not describe the system in the same manner. The results of this work suggest that the balance between intra- and intermolecular interactions is the cause of the differences between implicit and explicit solvent simulations in this system, stressing the role of the environment to define properly the conformational profile of a peptide in solution.