Conformational analysis of short polar side-chain amino-acids through umbrella sampling and DFT calculations

Molecular and quantum mechanics calculations were carried out in a series of tripeptides (GXG, where X = D, N and C) as models of the unfolded states of proteins. The selected central amino acids, especially aspartic acid (D) and asparagine (N) are known to present significant average conformations in partially allowed areas of the Ramachandran plot, which have been suggested to be important in unfolded protein regions. In this report, we present the calculation of the propensity values through an umbrella sampling procedure in combination with the calculation of the NMR J-coupling constants obtained by a DFT model. The experimental NMR observations can be reasonably explained in terms of a conformational distribution where PP II and β basins sum up propensities above 0.9. The conformational analysis of the side chain dihedral angle (χ 1 ), along with the computation of 3 J(H α H β ), revealed a preference for the g − and g + rotamers. These may be connected with the presence of intermolecular H-bonding and carbonyl–carbonyl interactions sampled in the PP II and β basins. Taking into account all those results, it can be established that these residues show a similar behavior to other amino acids in short peptides regarding backbone φ,ψ dihedral angle distribution, in agreement with some experimental analysis of capped dipeptides.