QUBO Problem Formulation of Fragment-Based Protein-Ligand Flexible Docking.

Protein-ligand docking plays a significant role in structure-based drug discovery. This methodology aims to estimate the binding mode and binding free energy between the drug-targeted protein and candidate chemical compounds, utilizing protein tertiary structure information. Reformulation of this docking as a quadratic unconstrained binary optimization (QUBO) problem to obtain solutions via quantum annealing has been attempted. However, previous studies did not consider the internal degrees of freedom of the compound that is mandatory and essential. In this study, we formulated fragment-based protein-ligand flexible docking, considering the internal degrees of freedom of the compound by focusing on fragments (rigid chemical substructures of compounds) as a QUBO problem. We introduced four factors essential for fragment-based docking in the Hamiltonian: (1) interaction energy between the target protein and each fragment, (2) clashes between fragments, (3) covalent bonds between fragments, and (4) the constraint that each fragment of the compound is selected for a single placement. We also implemented a proof-of-concept system and conducted redocking for the protein-compound complex structure of Aldose reductase (a drug target protein) using SQBM+, which is a simulated quantum annealer. The predicted binding pose reconstructed from the best solution was near-native (RMSD = 1.26 Å), which can be further improved (RMSD = 0.27 Å) using conventional energy minimization. The results indicate the validity of our QUBO problem formulation.

CycPeptMPDB: A Comprehensive Database of Membrane Permeability of Cyclic Peptides.

Recently, cyclic peptides have been considered breakthrough drugs because they can interact with "undruggable" targets such as intracellular protein-protein interactions. Membrane permeability is an essential indicator of oral bioavailability and intracellular targeting, and the development of membrane-permeable peptides is a bottleneck in cyclic peptide drug discovery. Although many experimental data on membrane permeability of cyclic peptides have been reported, a comprehensive database is not yet available. A comprehensive membrane permeability database is essential for developing computational methods for cyclic peptide drug design. In this study, we constructed CycPeptMPDB, the first web-accessible database of cyclic peptide membrane permeability. We collected information on a total of 7334 cyclic peptides, including the structure and experimentally measured membrane permeability, from 45 published papers and 2 patents from pharmaceutical companies. To unambiguously represent cyclic peptides larger than small molecules, we used the hierarchical editing language for macromolecules notation to generate a uniform sequence representation of peptides. In addition to data storage, CycPeptMPDB provides several supporting functions such as online data visualization, data analysis, and downloading. CycPeptMPDB is expected to be a valuable platform to support membrane permeability research on cyclic peptides. CycPeptMPDB can be freely accessed at http://cycpeptmpdb.com.

Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations.

Cyclic peptides have attracted attention as a promising pharmaceutical modality due to their potential to selectively inhibit previously undruggable targets, such as intracellular protein-protein interactions. Poor membrane permeability is the biggest bottleneck hindering successful drug discovery based on cyclic peptides. Therefore, the development of computational methods that can predict membrane permeability and support elucidation of the membrane permeation mechanism of drug candidate peptides is much sought after. In this study, we developed a protocol to simulate the behavior in membrane permeation steps and estimate the membrane permeability of large cyclic peptides with more than or equal to 10 residues. This protocol requires the use of a more realistic membrane model than a single-lipid phospholipid bilayer. To select a membrane model, we first analyzed the effect of cholesterol concentration in the model membrane on the potential of mean force and hydrogen bonding networks along the direction perpendicular to the membrane surface as predicted by molecular dynamics simulations using cyclosporine A. These results suggest that a membrane model with 40 or 50 mol % cholesterol was suitable for predicting the permeation process. Subsequently, two types of membrane models containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 40 and 50 mol % cholesterol were used. To validate the efficiency of our protocol, the membrane permeability of 18 ten-residue peptides was predicted. Correlation coefficients of R > 0.8 between the experimental and calculated permeability values were obtained with both model membranes. The results of this study demonstrate that the lipid membrane is not just a medium but also among the main factors determining the membrane permeability of molecules. The computational protocol proposed in this study and the findings obtained on the effect of membrane model composition will contribute to building a schematic view of the membrane permeation process. Furthermore, the results of this study will eventually aid the elucidation of design rules for peptide drugs with high membrane permeability.

Large-Scale Membrane Permeability Prediction of Cyclic Peptides Crossing a Lipid Bilayer Based on Enhanced Sampling Molecular Dynamics Simulations.

Membrane permeability is a significant obstacle facing the development of cyclic peptide drugs. However, membrane permeation mechanisms are poorly understood. To investigate common features of permeable (and nonpermeable) designs, it is necessary to reproduce the membrane permeation process of cyclic peptides through the lipid bilayer. We simulated the membrane permeation process of 100 six-residue cyclic peptides across the lipid bilayer based on steered molecular dynamics (MD) and replica-exchange umbrella sampling simulations and predicted membrane permeability using the inhomogeneous solubility-diffusion model and a modified version of it. Furthermore, we confirmed the effectiveness of this protocol by predicting the membrane permeability of 56 eight-residue cyclic peptides with diverse chemical structures, including some confidential designs from a pharmaceutical company. As a result, a reasonable correlation between experimentally assessed and calculated membrane permeability of cyclic peptides was observed for the peptide libraries, except for strongly hydrophobic peptides. Our analysis of the MD trajectory demonstrated that most peptides were stabilized in the boundary region between bulk water and membrane and that for most peptides, the process of crossing the center of the membrane is the main obstacle to membrane permeation. The height of this barrier is well correlated with the electrostatic interaction between the peptide and the surrounding media. The structural and energetic features of the representative peptide at each vertical position within the membrane were also analyzed, revealing that peptides permeate the membrane by changing their orientation and conformation according to the surrounding environment.

Impact of cis- versus trans-Configuration of Butylene Carbonate Electrolyte on Microscopic Solid Electrolyte Interphase Formation Processes in Lithium-Ion Batteries.

The solid electrolyte interphase (SEI) film, which consists of the products of reduction reaction of the electrolyte, has a strong influence on the lifetime and safety of Li-ion batteries. Of particular importance when designing SEI films is its strong dependence on the electrolyte solvent. In this study, we focused on geometric isomers cis- and trans-2,3-butylene carbonates ( c/ t-BC) as model electrolytes. Despite their similar structures and chemical properties, t-BC-based electrolytes have been reported to enable the reversible reaction of graphite anodes [as in ethylene carbonate (EC)], whereas c-BC-based electrolytes cause the exfoliation of graphite [as in propylene carbonate (PC)]. To understand the microscopic origin of the different electrochemical behaviors of t-BC and c-BC, we applied Red Moon simulation to elucidate the microscopic SEI film formation processes. The results revealed that the SEI film formed in c-BC-based electrolytes contains fewer dimerized products, which are primary components of a good SEI film; this lower number of dimerized products can cause reduced film stability. As one of the origins of the decreased dimerization in c-BC, we identified the larger solvation energy of c-BC for the intermediate species and its smaller diffusion constant, which largely diminishes the dimerization. Moreover, the correlation among the Li+ intercalation behavior, nature of the SEI film, and strength of solvation was found to be common for EC/PC and t-BC/ c-BC electrolytes, confirming the importance of solvation of the intermediates in the stability of the SEI film. These results suggest that weakening the solvation of the intermediates is one possible way to stabilize the SEI film for better charge-discharge performance.

Concentration Effect of Fluoroethylene Carbonate on the Formation of Solid Electrolyte Interphase Layer in Sodium-Ion Batteries.

Fluoroethylene carbonate (FEC) is an effective additive to improve the performance of Na-ion batteries (NIB). A recent experimental study has shown that a small amount of FEC enhances the NIB performance, whereas increasing the FEC amount deteriorates the performance. Toward understanding the microscopic mechanism of this observation, the dependency of the solid electrolyte interphase (SEI) film formation on the FEC concentration has been investigated in a propylene carbonate (PC)-based electrolyte solution by using the Red Moon method. This method was able to reproduce successfully the experimental observations where a small amount of FEC makes SEI film stable. Further, the increase in FEC amounts decreased the stability of the SEI film and should lead to the decrease in the NIB lifetime during charge-discharge cycles. It was revealed that this is because of the insufficient organic dimer formation between the monomer products at the higher FEC concentration. Finally, it was reconfirmed theoretically that the appropriate adjustment of FEC additive amount is essential to develop the high-performance of NIB.

Red Moon methodology compatible with quantum mechanics/molecular mechanics framework: Application to solid electrolyte interphase film formation in lithium-ion battery system.

The Red Moon (RM) method [a hybrid Monte Carlo (MC)/molecular dynamics reaction method] is capable of realizing the practical atomistic simulation for complex chemical reaction systems beyond the range of application of the traditional molecular simulation techniques. In the RM method, the chemical reaction is treated stochastically based on the MC method. In the present study, to extend the applicability of the RM methodology, a new energy estimation method for the MC procedure has been proposed by using the quantum mechanics (QM)/molecular mechanics (MM) method. To validate its calculation reliability, we have examined it in a typical dimerization reaction in electrolytes of lithium-ion batteries (LIBs) and found that both solute internal energy and short-range solute-solvent interaction energy are significantly improved in comparison to the conventional energy estimation method using the MM method. As a practical application, we have dealt with the solid electrolyte interphase film formation in LIB, focusing on the bifurcation of dimerization reactions between the reduction products, and were able to reproduce the tendency similar to that in the experimental observations. It is concluded that the present RM methodology compatible with the QM/MM framework is expected to make a significant contribution to a variety of materials design and function development involved in various complex chemical reactions.