A General Picture of Cucurbit[8]uril Host-Guest Binding: Recalibrating Bonded Interactions.

Atomic-level understanding of the dynamic feature of host-guest interactions remains a central challenge in supramolecular chemistry. The remarkable guest binding behavior of the Cucurbiturils family of supramolecular containers makes them promising drug carriers. Among Cucurbit[n]urils, Cucurbit[8]uril (CB8) has an intermediate portal size and cavity volume. It can exploit almost all host-guest recognition motifs formed by this host family. In our previous work, an extensive computational investigation of the binding of seven commonly abused and structurally diverse drugs to the CB8 host was performed, and a general dynamic binding picture of CB8-guest interactions was obtained. Further, two widely used fixed-charge models for drug-like molecules were investigated and compared in great detail, aiming at providing guidelines in choosing an appropriate charge scheme in host-guest modelling. Iterative refitting of atomic charges leads to improved binding thermodynamics and the best root-mean-squared deviation from the experimental reference is 2.6 kcal/mol. In this work, we focus on a thorough evaluation of the remaining parts of classical force fields, i.e., the bonded interactions. The widely used general Amber force fields are assessed and refitted with generalized force-matching to improve the intra-molecular conformational preference, and thus the description of inter-molecular host-guest interactions. The interaction pattern and binding thermodynamics show a significant dependence on the modelling parameters. The refitted system-specific parameter set improves the consistency of the modelling results and the experimental reference significantly. Finally, combining the previous charge-scheme comparison and the current force-field refitting, we provide general guidelines for the theoretical modelling of host-guest binding.

Seeding the multi-dimensional nonequilibrium pulling for Hamiltonian variation: indirect nonequilibrium free energy simulations at QM levels.

The combination of free energy simulations in the alchemical and configurational spaces provides a feasible route to access the thermodynamic profiles under a computationally demanding target Hamiltonian. Normally, due to the significant differences between the computational cost of ab initio quantum mechanics (QM) calculations and those of semi-empirical quantum mechanics (SQM) and molecular mechanics (MM), this indirect method could be used to obtain the QM thermodynamics by combining the SQM or MM results and the SQM-to-QM or MM-to-QM corrections. In our previous work, a multi-dimensional nonequilibrium pulling framework for Hamiltonian variations was introduced based on bidirectional pulling and bidirectional reweighting. The method performs nonequilibrium free energy simulations in the configurational space to obtain the thermodynamic profile along the conformational change pathway under a selected computationally efficient Hamiltonian, and uses the nonequilibrium alchemical method to correct or perturb the thermodynamic profile to that under the target Hamiltonian. The BAR-based method is designed to achieve the best generality and transferability and thus leads to modest (∼20 fold) speedup. In this work, we explore the possibility of further accelerating the nonequilibrium free energy simulation by employing unidirectional pulling and using the selection criterion to obtain the initial configurations used to initiate nonequilibrium trajectories following the idea of adaptive steered molecular dynamics (ASMD). A single initial condition is used to seed the whole multi-dimensional nonequilibrium free energy simulation and the sampling is performed fully in the nonequilibrium ensemble. Introducing very short ps-length equilibrium sampling to grab more initial seeds could also be helpful. The ASMD scheme estimates the free energy difference with the unidirectional exponential average (EXP), but it does not follow exactly the requirements of the EXP estimator. Another deficiency of the seeding simulation is the inherently sequential or serial pulling due to the inter-segment dependency, which triggers some problems in the parallelizability of the simulation. Numerical tests are performed to grasp some insights and guidelines for using this selection-criterion-based ASMD scheme. The presented selection-criterion-based multi-dimensional ASMD scheme follows the same perturbation network of the BAR-based method, and thus could be used in various Hamiltonian-variation cases.

A General Picture of Cucurbit[8]uril Host-Guest Binding.

Describing, understanding, and designing complex interaction networks within macromolecular systems remain challenging in modern chemical research. Host-guest systems, despite their relative simplicity in both the structural feature and interaction patterns, still pose problems in theoretical modeling. The barrel-shaped supramolecular container cucurbit[8]uril (CB8) shows promising functionalities in various areas, e.g., catalysis and molecular recognition. It can stably coordinate a series of structurally diverse guests with high affinities. In this work, we examine the binding of seven commonly abused drugs to the CB8 host, aiming at providing a general picture of CB8-guest binding. Extensive sampling of the configurational space of these host-guest systems is performed, and the binding pathway and interaction patterns of CB8-guest complexes are investigated. A thorough comparison of widely used fixed-charge models for drug-like molecules is presented. Iterative refitting of the atomic charges suggests significant conformation dependence of charge generation. The initial model generated at the original conformation could be inaccurate for new conformations explored during conformational search, and the newly fitted charge set improves the prediction-experiment correlation significantly. Our investigations of the configurational space of CB8-drug complexes suggest that the host-guest interactions are more complex than expected. Despite the structural simplicities of these molecules, the conformational fluctuations of the host and the guest molecules and orientations of functional groups lead to the existence of an ensemble of binding modes. The insights of the binding thermodynamics, performance of fixed-charge models, and binding patterns of the CB8-guest systems are useful for studying and elucidating the binding mechanism of other host-guest complexes.

SAMPL6 host-guest binding affinities and binding poses from spherical-coordinates-biased simulations.

Host-guest binding is a challenging problem in computer simulation. The prediction of binding affinities between hosts and guests is an important part of the statistical assessment of the modeling of proteins and ligands (SAMPL) challenges. In this work, the volume-based variant of well-tempered metadynamics is employed to calculate the binding affinities of the host-guest systems in the SAMPL6 challenge. By biasing the spherical coordinates describing the relative position of the host and the guest, the initial-configuration-induced bias vanishes and all possible binding poses are explored. The agreement between the predictions and the experimental results and the observation of new binding poses indicate that the volume-based technique serves as a nice candidate for the calculation of binding free energies and the search of the binding poses.

BAR-based multi-dimensional nonequilibrium pulling for indirect construction of a QM/MM free energy landscape.

Construction of free energy landscapes at the quantum mechanics (QM) level is computationally demanding. As shown in previous studies, by employing an indirect scheme (i.e. constructing a thermodynamic cycle connecting QM states via an alchemical pathway), simulations are converged with much less computational burden. The indirect scheme makes QM/molecular mechanics (MM) free energy simulation orders of magnitude faster than the direct QM/MM schemes. However, the indirect QM/MM simulations were mostly equilibrium sampling based and the nonequilibrium methods were merely exploited in one-dimensional alchemical QM/MM end-state correction at two end states. In this work, we represent a multi-dimensional nonequilibrium pulling scheme for indirect QM/MM free energy simulations, where the whole free energy simulation is performed only with nonequilibrium methods. The collective variable (CV) space we explore is a combination of one alchemical CV and one physically meaningful CV. The current nonequilibrium indirect QM/MM simulation method can be seen as the generalization of equilibrium perturbation based indirect QM/MM methods. The test systems include one backbone dihedral case and one distance case. The two cases are significantly different in size, enabling us to investigate the dependence of the speedup of the indirect scheme on the size of the system. It is shown that the speedup becomes larger when the size of the system becomes larger, which is consistent with the scaling behavior of QM Hamiltonians.

Sulfur-substitution-induced base flipping in the DNA duplex.

Base flipping is widely observed in a number of important biological processes. The genetic codes deposited inside the DNA duplex become accessible to external agents upon base flipping. The sulfur substitution of guanine leads to thioguanine, which alters the thermodynamic stability of the GC base pairs and the GT mismatches. Experimental studies conclude that the sulfur substitution decreases the lifetime of the GC base pair. In this work, under three AMBER force fields for nucleotide systems, we firstly performed equilibrium and nonequilibrium free energy simulations to investigate the variation of the thermodynamic profiles in base flipping upon sulfur substitution. It is found that the bsc0 modification, the bsc1 modification and the OL15 modification of AMBER force fields are able to qualitatively describe the sulfur-substitution dependent behavior of the thermodynamics. However, only the two last-generation AMBER force fields are able to provide quantitatively correct predictions. The second computational study on the sulfur substitutions focused on the relative stability of the S6G-C base pair and the S6G-T mismatch. Two conflicting experimental observations were reported by the same authors. One suggested that the S6G-C base pair was more stable, while the other concludes that the S6G-T mismatch was more stable. We answered this question by constructing the free energy profiles along the base flipping pathway computationally.