Evaluating the Performance of Water Models with Host–Guest Force Fields in Binding Enthalpy Calculations for Cucurbit[7]uril–Guest Systems

Abstract

Computational prediction of thermodynamic components with computational methods has become increasingly routine in computer-aided drug design. Although, there has been significant recent effort and improvements in the calculation of free energy, the prediction of enthalpy (and entropy) remains under-explored. Furthermore, there has been relatively little work reported so far that attempts to comparatively assess how well different force-fields and water models perform in conjunction with each other. Here, we report a comprehensive assessment of force fields and water models using host-guest systems that mimic many features of protein-ligand systems. These systems are computationally inexpensive possible because of their small size compared to protein-ligand systems. We present absolute enthalpy calculations using the multi-box approach on a set of 25 cucurbit[7]uril-guest pairs. Eight water models were considered (TIP3P, TIP4P, TIP4P-Ew, SPC, SPC/E, OPC, TIP5P, Bind3P), along with five force fields commonly used in the literature (GAFFv1, GAFFv2, CGenFF, Parsley and SwissParam). We observe that host-guest binding enthalpies are strongly sensitive to the selection of force-field and water model. In terms of water models, we find that TIP3P, and its derivative Bind3P are the best performing models for this particular host-guest system. The performance is generally better for aliphatic compounds than aromatic ones, suggesting aromaticity remains a difficult property to include accurately in these simple force fields.

Influence of water models on water movement through AQP1

“…Recently a number of studies have addressed the relevance of water models in e.g. protein aggregation and host-guest recognition systems 37,59 . Our main purpose was to compare among the behaviour of different water models and shed light on AQP1 water permeability.…”

“…It is therefore beneficial to first assess the consistency and accuracy of a range of rigid non-polarizable models in order to establish whether the use of polarizable water models is needed for the study of water behaviour in aquaporins. Similar comparisons of non-polarizable water models have been conducted for the 5-HT3 receptor channel 36 and Cucurbit [7]uril-guest systems 37 . In this article, we have studied several properties of human AQP1 (water diffusion across the pore, diffusion permeability and osmotic permeability) taking into account the molecular mechanism characteristic of AQP.…”

Water Nanoconfined in a Hydrophobic Pore: Molecular Dynamics Simulations of Transmembrane Protein 175 and the Influence of Water Models

“… 35 The effect of polarizable water models within synthetic nanoconfined environments under an electric field has also been investigated, with the conclusion that polarizability can affect the structure and dynamics of the systems. 36 – 38 Various rigid fixed-charge water models have also been assessed for ligand binding in host/guest systems 39 and for water behaviour in peptide nanotubes. 29 …”

“…Although polarizable models are more computationally expensive, the development of more powerful computing facilities and of improved software enables the use of such models for complex biological systems. , Thus, recent studies have explored the influence of polarizable models on, for example, simulations of the interactions of ions with lipid bilayer membranes, simple model ion channels, and on electric field strength within the active site of an enzyme . The effect of polarizable water models within synthetic nanoconfined environments under an electric field has also been investigated, with the conclusion that polarizability can affect the structure and dynamics of the systems. − Various rigid fixed-charge water models have also been assessed for ligand binding in host/guest systems and for water behavior in peptide nanotubes …”

Water Nanoconfined in a Hydrophobic Pore: MD Simulations and Water Models

“…31 . Various rigid fixed-charge water models have also been assessed for ligand binding in host/guest systems 32 and for water behaviour in peptide nanotubes 26 . Wetting/de-wetting of a hydrophobic gate provides an extreme case of non-bulk behaviour of water when nanoconfined in a pore.…”