The CHARMM Drude-2013 polarizable force field (FF) was developed to include the explicit treatment of induced electronic polarizability, resulting in a more accurate description of the electrostatic interactions in molecular dynamics (MD) simulations. While the Drude-2013 protein FF has shown success in improving the folding properties of α-helical peptides and to reproduce experimental observables in simulations up to 1 μs, some limitations were noted regarding the stability of β-sheet structures in simulations longer than 100 ns as well as larger deviations from crystal structures in simulations of a number of proteins compared to the additive CHARMM36 protein FF. The origin of the instability has been identified and appears to be primarily due to overestimated atomic polarizabilities and induced dipole–dipole interactions on the Cβ, Cγ, and Cδ side chain atoms. To resolve this and other issues, a number of aspects of the model were revisited, resulting in Drude-2019 protein FF. Backbone parameters were optimized targeting the conformational properties of the (Ala)5 peptide in solution along with gas phase properties of the alanine dipeptide. Dipeptides that contain N-acetylated and N′-methylamidated termini, excluding Gly, Pro, and Ala, were used as models to optimize the atomic polarizabilities and Thole screening factors on selected Cβ, Cγ, and Cδ carbons by targeting quantum mechanical (QM) dipole moments and molecular polarizabilities. In addition, to obtain better conformational properties, side chain χ1 and χ2 dihedral parameters were optimized targeting QM data for the respective side chain dipeptide conformations as well as Protein Data Bank survey data based on the χ1, χ2 sampling from Hamiltonian replica-exchange MD simulations of (Ala)4-X-(Ala)4 in solution, where X is the amino acid of interest. Further improvements include optimizing nonbonded interactions between charged residues to reproduce QM interaction energies of the charged-protein model compounds and experimental osmotic pressures. Validation of the optimized Drude protein FF includes MD simulations of a collection of peptides and proteins including β-sheet structures, as well as transmembrane ion channels. Results showed that the updated Drude-2019 protein FF yields smaller overall root-mean-square differences of proteins as compared to the additive CHARMM36m and Drude-2013 FFs as well as similar or improved agreement with experimental NMR properties, allowing for long time scale simulation studies of proteins and more complex biomolecular systems in conjunction with the remainder of the Drude polarizable FF.

Halogens are present in a significant number of drugs, contributing favorably to ligand–protein binding. Currently, the contribution of halogens, most notably chlorine and bromine, is largely attributed to halogen bonds involving favorable interactions with hydrogen bond acceptors. However, we show that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations. In addition, bioinformatics analysis of ligand–protein crystal structures shows the presence of significant numbers of such interactions. It is shown that interactions between halogens and hydrogen bond donors (HBDs) are dominated by perpendicular C–X···HBD orientations. Notably, the orientation dependence of the halogen–HBD (X–HBD) interactions is minimal over greater than 100° with favorable interaction energies ranging from −2 to −14 kcal/mol. This contrasts halogen bonds in that X–HBD interactions are substantially more favorable, being comparable to canonical hydrogen bonds, with a smaller orientation dependence, such that they make significant, favorable contributions to ligand–protein binding and, therefore, should be actively considered during rational ligand design.

BACE1 is a major therapeutic target for prevention and treatment of Alzheimer’s disease. Developing inhibitors that can selectively target BACE1 in favor of other proteases, especially cathepsin D (CatD), has presented significant challenges. Here we investigate the conformational dynamics and protonation states of BACE1 and CatD using continuous constant pH molecular dynamics with pH replica-exchange sampling protocol. Despite similar structure, BACE1 and CatD exhibit markedly different active site dynamics. BACE1 displays pH-dependent flap dynamics that controls substrate accessibility, while the CatD flap is relatively rigid and remains open in the pH range 2.5–6. Interestingly, although each protease hydrolyzes peptide bonds, the protonation states of the catalytic dyads are different within the active pH range. The acidic and basic components of the BACE1 catalytic dyad are clear, while either aspartic acid of the CatD catalytic dyad could play the role of acid or base. Finally, we investigate binding of the inhibitor LY2811376 developed by Eli Lilly to BACE1 and CatD. Surprisingly, in the enzyme active pH range, LY2811376 forms a stronger salt bridge with the catalytic dyad in CatD than in BACE1, which might explain the retinal toxicity of the inhibitor related to off-target inhibition of CatD. This work highlights the complexity and challenge in structure-based drug design where receptor-ligand binding induces protonation state change in both the protein and the inhibitor.

Development of accurate force field parameters for molecular ions in the context of a polarizable energy function based on the classical Drude oscillator is a crucial step toward an accurate polarizable model for modeling and simulations of biological macromolecules. Toward this goal we have undertaken a hierarchical approach in which force field parameter optimization is initially performed for small molecules for which experimental data exists that serve as building blocks of macromolecular systems. Small molecules representative of the ionic moieties of biological macromolecules include the cationic ammonium and methyl substituted ammonium derivatives, imidazolium, guanidinium and methylguanidinium, and the anionic acetate, phenolate, and alkanethiolates. In the present work, parameters for molecular ions in the context of the Drude polarizable force field are optimized and compared to results from the nonpolarizable additive CHARMM general force field (CGenFF). Electrostatic and Lennard-Jones parameters for the model compounds are developed in the context of the polarizable SWM4-NDP water model, with emphasis on assuring that the hydration free energies are consistent with previously reported parameters for atomic ions. The final parameters are shown to be in good agreement with the selected quantum mechanical (QM) and experimental target data. Analysis of the structure of water around the ions reveals substantial differences between the Drude and additive force fields indicating the important role of polarization in dictating the molecular details of aqueous solvation. The presented parameters represent the foundation for the charged functionalities in future generations of the Drude polarizable force field for biological macromolecules as well as for drug-like molecules.

The quality of the force field is crucial to ensure the accuracy of simulations used in molecular modeling, including computer-aided drug design (CADD). To perform more accurate modeling and simulations of halogenated molecules, in this study the polarizable force field based on the classical Drude oscillator model was extended to both aliphatic and aromatic systems using halogenated ethane and benzene model compounds for the halogens F, Cl, Br, and I. The force field parameters were optimized targeting quantum mechanical dipole moments, water interactions, and molecular polarizabilities as well as experimental observables, including enthalpies of vaporization, molecular volumes, hydration free energies, and dielectric constants. The developed halogenated polarizable force field is capable of reproducing QM relative energies and geometries of both halogen bonds and halogen-hydrogen bond donor interactions at an unprecedented level due to the inclusion of a virtual particle and anisotropic atomic polarizability on the halogen and, notably, the inclusion of Lennard-Jones parameters on the halogen Drude particle. The model was validated on the basis of its ability to accurately reproduce pure solvent properties for halogenated naphthalenes and alkanes, including species analogous to those used as refrigerants. Accordingly, it is anticipated that the model will be applicable for the study of halogenated derivatives in CADD as well as in other chemical and biophysical studies.