Do molecular dynamics force fields accurately model Ramachandran distributions of amino acid residues in water?

Abstract

Molecular dynamics (MD) is a powerful tool for studying intrinsically disordered proteins, however, its reliability depends on the accuracy of the force field. We here assess Amber ff14SB, Amber ff14SB,...

How do salt and lipids affect conformational dynamics of Aβ42 monomers in water?

“…Alanine (A21, A30), lysines (K16, K28), and glutamic acid (E11, E22) residues, for example, all exhibit high MD-derived 3 J(H N , H C α ) values, implying a significantly higher population of extended structures in MD relative to experimental values. The strong preference for the pPII structure of valine and isoleucine in CHARMM36m (and many other MD force fields), as reported in our previous work, 35 and a failure to account for the nearest neighboring effects on conformational preferences in the absence of non-local interactions 67 could explain the above observations. A similar argument can be made for aspartic acid residues.…”

“…CHARMM36m as well as most other MD force fields overly promote pPII content in polar and ionizable residues at the expense of extended or turn-like structures predicted experimentally. 35 These low J -coupling constant values could also be explained by an increase of right-handed helical structures for these amino acid residues. However, Fig.…”

“…We here examine the effect of salt and DMPC lipids on fully atomistic Aβ42 monomer conformations using CHARMM36m and its innate TIP3P water model, which was shown to perform optimally based on comparison to available spectroscopic data on short unfolded peptides when compared to other modern force fields. 31,33–35,67…”

“…28,29 In this paper, we employ CHARMM36m 30 which was shown to be one of the most reliable MD force fields for modeling short unfolded peptides, [31][32][33][34] although lacking amino acid specificity in reproducing experimentally-derived Ramachandran distributions of residues in water. 35 In vivo, Ab42 exerts its activity in the presence of physiological levels of salt and other biomolecules. We here ask, to which extent physiological levels of salt and the presence of free lipids affect Ab42 folding dynamics.…”

Exploring Nearest Neighbor Interactions and Their Influence on the Gibbs Energy Landscape of Unfolded Proteins and Peptides

“…Third, given the relevance of MD simulations for the study of IDPs and their biological functions, the utilized force field should be able to account for the influence of NNIs. In view of the fact that most of the current force fields cannot even properly reproduce experimental data of model peptides [ 25 , 26 , 130 ], the field is not even close to achieving this goal. Fourth, it is very likely that residual structures of protein segments are relevant for the initial phase of protein folding and peptide/protein self-assembly [ 131 , 132 , 133 ].…”