Reparameterization of Solute—Solute Interactions for Amino Acid–Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations

Abstract

AMBER/GLYCAM and CHARMM are popular force fields for simulations of amino acids and sugars. Here we report excessively attractive amino acid-sugar interactions in both force fields, and corrections to nonbonded interactions that match experimental osmotic pressures of mixed aqueous solutions of diglycine and sucrose. The modified parameters also improve the ΔGtrans of diglycine from water to aqueous sucrose and, with AMBERff99SB/GLYCAM06, eliminate a caging effect seen in previous simulations of the protein ubiquitin with glucose.

Molecular dynamics insights into protein‐glycosaminoglycan systems from microsecond‐scale simulations

“…The observed significant conformational changes after the 6th μs could reflect the realistic scenario corresponding to the FGF‐HE complex conformation in a significantly lower energetic state in comparison to the starting experimental structure similarly to the CD44‐hyaluronic acid complex analyzed by Vuorio et al However, it is not completely excluded that such an observation could be a result of the force field applied to the system. In particular, it was previously demonstrated that the combination of AMBERff99SB and GLYCAM06 reveals excessively attractive interactions between the amino acids and saccharides, which lead to the need for correcting the nonbonded terms of the force fields in order to achieve an agreement with the experimentally obtained osmotic pressures for diglycine and sucrose mixtures . Therefore, the new binding pose and new contacts obtained in our long MD simulation should be interpreted with care since they could potentially appear as a consequence of the above‐mentioned force field in combination with limitations, rather than representing a more energetically favorable structure that could indeed occur in nature.…”

“…The severe conformational change in the FGF‐HE complex observed in the simulation at the 6th microsecond was characterized in terms of free energy, HE flexibility, and the fraction of native contacts in the complexes as well as by glycosidic linkages and ring puckering conformational changes. Altogether this finding suggests that the long microsecond‐scale MD simulations could yield principally different results when compared to the nanosecond‐scale ones, it is not excluded that such an observation of a conformational change is due to the internal limitations of the used force field, which could be pronounced only in longer simulations. From a methodological point of view, we described which parameters obtained from the MD simulations are different and which are the same when comparing nanosecond‐ and microsecond‐scale MD simulations, which is significant for the setup of an in silico experiment aimed at dealing with a particular property of a protein‐GAG system.…”

Reparametrization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements from Molecular Dynamics Simulations

“…4 Since then, osmotic coefficients and pressures have been used to reparametrize other salts, 5–6 organic ions, 7–8 carbohydrates, 9–10 and even amino acid-carbohydrate systems. 11 Still, the use of osmotic coefficients to parameterize molecular interactions remains in a nascent stage, which allows for a great deal of exploration and investigation.…”

Use of osmotic coefficient measurements to validate and to correct the interaction thermodynamics of amino acids in molecular dynamics simulations

“…[17][18][19][20] To do so, the interactions of amino acids or their small molecule analogs were examined using a virtual osmotic pressure apparatus. This simulation tool was first proposed nearly 25 years ago 86 and was subsequently implemented by a number of groups, including our own through the efforts of Wesley Lay 93,143 and myself. [12][13] Using this simulation technique, any small molecule can be screened and assessed, provided there are osmotic coefficient (or analogous) data available in the literature against which to compare.…”

“…58 Since then, osmotic coefficients and pressures have been used to reparametrize other salts, 53,88 organic ions, 87,89 carbohydrates, 90,92 and even amino acid-carbohydrate systems. 93 Still, the use of osmotic coefficients to parameterize molecular interactions remains in a nascent stage, which allows for a great deal of exploration and investigation.…”