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

Atomic-level understanding of the dynamical 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 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 7 commonly abused and structurally diverse drugs to the CB8 host was performed and a general dynamical 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 to improve the intra-molecular conformational preference and thus the description of inter-molecular host-guest interactions. The interaction pattern and binding thermodynamics show 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.

Protein-protein interaction-Gaussian accelerated molecular dynamics (PPI-GaMD): Characterization of protein binding thermodynamics and kinetics

Protein-protein interactions (PPIs) play key roles in many fundamental biological processes such as cellular signaling and immune responses. However, it has proven challenging to simulate repetitive protein association and dissociation in order to calculate binding free energies and kinetics of PPIs, due to long biological timescales and complex protein dynamics. To address this challenge, we have developed a new computational approach to all-atom simulations of PPIs based on a robust Gaussian accelerated molecular dynamics (GaMD) technique. The method, termed "PPI-GaMD", selectively boosts interaction potential energy between protein partners to facilitate their slow dissociation. Meanwhile, another boost potential is applied to the remaining potential energy of the entire system to effectively model the protein's flexibility and rebinding. PPI-GaMD has been demonstrated on a model system of the ribonuclease barnase interactions with its inhibitor barstar. Six independent 2 µs PPI-GaMD simulations have captured repetitive barstar dissociation and rebinding events, which enable calculations of the protein binding thermodynamics and kinetics simultaneously. The calculated binding free energies and kinetic rate constants agree well with the experimental data. Furthermore, PPI-GaMD simulations have provided mechanistic insights into barstar binding to barnase, which involve long-range electrostatic interactions and multiple binding pathways, being consistent with previous experimental and computational findings of this model system. In summary, PPI-GaMD provides a highly efficient and easy-to-use approach for binding free energy and kinetics calculations of PPIs.

Solution NMR of Nanoparticles in Serum: Protein Competition Influences Binding Thermodynamics and Kinetics

The spontaneous formation of a protein corona on a nanoparticle surface influences the physiological success or failure of the synthetic nanoparticle as a drug carrier or imaging agent used in vivo. A quantitative understanding of protein-nanoparticle interactions is therefore critical for the development of nanoparticle-based therapeutics. In this perspective, we briefly discuss the challenges and limitations of current approaches used for studying protein-nanoparticle binding in a realistic biological medium. Subsequently, we demonstrate that solution nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to monitor protein competitive binding in a complex serum medium in situ. Importantly, when many serum proteins are competing for a gold nanoparticle (AuNP) surface, solution NMR is able to detect differences in binding thermodynamics, and kinetics of a tagged protein. Combined with other experimental approaches, solution NMR is an invaluable tool to understand protein behavior in the nanoparticle corona.

Different phosphorylation and farnesylation patterns tune Rnd3–14-3-3 interaction in distinct mechanisms

Different protein posttranslational modifications (PTMs) patterns affect the binding thermodynamics and kinetics and their molecular mechanism of multivalent protein–protein interaction (PPIs).