The role of water in host-guest interaction

Abstract

One of the main applications of atomistic computer simulations is the calculation of ligand binding energies. The accuracy of these calculations depends on the force field quality and on the thoroughness of configuration sampling. Sampling is an obstacle in modern simulations due to the frequent appearance of kinetic bottlenecks in the free energy landscape. Very often this difficulty is circumvented by enhanced sampling techniques. Typically, these techniques depend on the introduction of appropriate collective variables that are meant to capture the system's degrees of freedom. In ligand binding, water has long been known to play a key role, but its complex behaviour has proven difficult to fully capture. In this paper we combine machine learning with physical intuition to build a non-local and highly efficient water-describing collective variable. We use it to study a set of of host-guest systems from the SAMPL5 challenge. We obtain highly accurate binding energies and good agreement with experiments. The role of water during the binding process is then analysed in some detail.

Collective variable discovery in the age of machine learning: reality, hype and everything in between

“…linearity. Recently Deep-LDA framework has been applied in SAMPL5 host-guest systems to accurately calculate binding free energy and to understand the role of water molecule in ligand binding (64 ).…”

“…Recently numerous papers reported different combinations of abstract order parameters to capture conformational dynamics and molecular recognition of macromolecules. In one such case neural network based LDA (Deep-LDA) approach has been applied on SAMPL5 hostguest systems to estimate binding free energy (64 ). Previously funnel metadynamics using simple distance CV combined with artificial restraint along binding-site solvation managed to accurately predict the binding free energy for the same host-guest systems (68 ).…”

Adaptive insertion of the hydrophobic anchor into poly(ethylene glycol) host for programmable surface functionalization

“…However, unlike the existence of a hydrophobic cavity in cyclodextrins and cucurbiturils for binding, PEG chains are well hydrated in an aqueous medium by forming hydrogen bonds with water molecules [22][23][24] . The association of a guest molecule and PEG should require the breakage of these hydrogen bonds and the removal of water molecules from the binding site, just like the protein-ligand binding [25][26][27] . The dehydration of PEG was thought very di cult, due to its high aqueous solubility 28 .…”

Molecular Environment Specific Atomic Charges Improve Binding Affinity Predictions of SAMPL5 Host-Guest Systems

“…9 These host-guest systems represent a standard benchmark set used by the computer simulation community to assess varying methodologies. 10 The reduced flexibility and small size of host-guest systems has also stimulated new efficient algorithms and simulation protocols reducing the error from sampling and the differences between varying software packages. 2,4,6,7,[11][12][13][14][15][16][17][18][19] Yet, the computationally-efficient correct description of the molecular interactions by force fields presents an open challenge for binding host-guest predictions.…”