Abstract
In this study, we report binding free energy calculations of various drugs-of-abuse to Cucurbit-[8]-uril as part of the SAMPL8 blind challenge. Force-field parameters were obtained from force-matching with different quantum mechanical levels of theory. The Replica Exchange Umbrella Sampling (REUS) approach was used with a cylindrical restraint to enhance the sampling of host–guest binding. Binding free energy was calculated by pulling the guest molecule from one side of the symmetric and cylindrical host, then into and through the host, and out the other side (bidirectional) as compared to pulling only to the bound pose inside the cylindrical host (unidirectional). The initial results with force-matched MP2 parameter set led to RMSE of 4.68 {text{kcal}}/{text{mol}} from experimental values. However, the follow-up study with CHARMM generalized force field parameters and force-matched PM6-D3H4 parameters resulted in RMSEs from experiment of 2.65 and 1.72 {text{kcal}}/{text{mol}}, respectively, which demonstrates the potential of REUS for accurate binding free energy calculation given a more suitable description of energetics. Moreover, we compared the free energies for the so called bidirectional and unidirectional free energy approach and found that the binding free energies were highly similar. However, one issue in the bidirectional approach is the asymmetry of profile on the two sides of the host. This is mainly due to the insufficient sampling for these larger systems and can be avoided by longer sampling simulations. Overall REUS shows great promise for binding free energy calculations.
Highlights
Binding free energy prediction between a receptor and a ligand is a crucial task for small-molecule drug discovery, and computational techniques have recently found great utility for this pivotal task [1,2,3]
The reaction coordinate in all simulations is the distance between the center of mass of the heavy atoms of the guest molecule and the carbonyl oxygen atoms of the left side of cylindrical host projected along the principal z axis of the cylindrical restraint around the host
A bidirectional reaction coordinate was adopted for all systems where replicas are initiated in both sides of the cylindrical host except for G2 system in FM-MP2 force-matched parameter set
Summary
Binding free energy prediction between a receptor and a ligand is a crucial task for small-molecule drug discovery, and computational techniques have recently found great utility for this pivotal task [1,2,3]. A major goal of computer-aided drug design is to decrease the time and cost of lead optimization. This requires a detailed understanding of the intrinsic protein–ligand interactions, which are mainly studied via free energy calculation methods. Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) blind challenges have provided a unique opportunity to validate different computational methods for quantitative prediction of binding free energies
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