Experimental work developed in the last years has evidenced the capacity of alcohols and polyalcohols to modify the energy landscape of peptides and proteins. However, the mechanism underlying this effect is not clear. Taking as a model system the alanine dipeptide (AD) we perform a QM/MM study in water, ethanol, and a 40-60% in volume water-ethanol mixture. The AD molecule was described at the MP2/aug-cc-pVDZ level. In polar solution, only αR and PPII conformers contribute in an appreciable way to the conformational equilibrium. The final in solution αR-PPII free energy difference is determined from the interplay between the internal energy of the dipeptide and the solute-solvent interaction free energy. Internal energy favors the formation of PPII, whereas, on the contrary, solute-solvent interaction is favorable to αR, so any factor that decreases the solute-solvent interaction free energy will increase the PPII population. The addition of ethanol increases the stability of the PPII conformer. Our results point to the presence of preferential solvation in this system, the composition of the first solvation shell in the binary mixture being dominated by water molecules. Remarkably, this fact does not affect the differential conformational stability that is controlled by long-range interactions. From the analysis of solvent density maps it is concluded that, in the water-ethanol mixture, ethanol molecules are more likely found around the alanine side chain and the carbonyl group, but while in PPII ethanol molecules interact mainly with the carbonyl group of the N-terminal end, in C5 the interaction is with the carbonyl group of the C-terminal end. In αR, ethanol interacts with both carbonyl groups.

Os líquidos N-metilformamida e acetona foram revisitados através de simulações Monte Carlo feitas no ensemble NPT, a 1 atm e 25 °C. As moléculas são rígidas com todos os átomos explicitados e o potencial intermolecular utilizado é o clássico 6-12 Lennard-Jones mais Coulomb. Os g(r)'s teóricos dos dois líquidos foram comparados com aqueles obtidos através de difratometria de nêutrons e simulação de refinamento de estrutura. Os resultados indicam a existência de ligações de hidrogênio determinando a estrutura da N-metilformamida, enquanto que na acetona as correlações são orientadas pelo momento dipolar. A estrutura do líquido N-metilformamida é guiada por um dímero preponderante, no qual as moléculas estão posicionadas de maneira que o ângulo entre os vetores de dipolo é 73°, enquanto que no líquido acetona, que é muito menos organizado, a orientação dos dipolos das moléculas muda de antiparalela a curtas distâncias para mais paralela à medida que a distância aumenta.The pure liquids N-methylformamide and acetone have been revisited via Monte Carlo simulations in the NTP ensemble at 1 atm and 25 °C. The molecules are all-atom rigid structures, and the intermolecular potential used is the classical 6-12 Lennard-Jones plus Coulomb. The theoretical g(r)s of both liquids were compared with those obtained from neutron diffraction and empirical potential structure refinement simulations. The results point to the existence of H-bonds driving the N-methylformamide structure, while in acetone the correlations are dipole moment oriented. The structure of the liquid N-methylformamide is mainly guided by a dimer whose molecules are arranged in such a way that the angle between their dipole moments is 73°, while liquid acetone is much less organized and the orientation of the molecules changes from an antiparallel dipolar correlation at short distances to more parallel alignments of the molecular dipole moments for larger distances.Keywords: Monte Carlo, acetone, N-methylformamide, hydrogen bonds, liquid structure Introduction N-methylformamide (NMF) and acetone (ACT) belong to a group of dipolar organic solvents, which are common media for a variety of important chemical reactions. Table 1 shows some of the most common physical-chemistry properties of the liquids to give an idea of the differences.NMF is one of the simplest molecules among those that include a peptide bond in their structure. The molecule has long been of great interest because of the presence of that structure as a repeat unit in proteins and peptides. The liquid, either pure or as a component of mixtures, has been the subject of studies, theoretically [2][3][4][5][6][7][8][9][10] as well as experimentally. [11][12][13][14][15][16][17][18] The NMF molecules act as proton donors and acceptors via their C=O and H-N groups and consequently form C=O•••H-N hydrogen bonds (H-bond) with each other, the same type of H-bond that is known to play an important role in stabilizing the ordered intramolecular structure of peptides and proteins.19 Moreover, these molecule...

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