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The Adaptive Solvent-Scaling (AdSoS) scheme [J. Chem. Phys. 155 (2021) 094107] is an adaptive-resolution approach for performing simulations of a solute embedded in a fine-grained (FG) solvent region surrounded by a coarse-grained (CG) solvent region, with a continuous FG ↔ CG switching of the solvent resolution across a buffer layer. Instead of relying on a distinct CG solvent model, AdSoS is based on CG models defined by a dimensional scaling of the FG solvent by a factor s, accompanied by the s-dependent modulation of its mass and interaction parameters. The latter changes are designed to achieve an isomorphism between the dynamics of the FG and CG models, and to preserve the dispersive and dielectric solvation properties of the solvent with respect to a solute at FG resolution. As a result, the AdSoS scheme minimizes the thermodynamic mismatch between different regions of the adaptive-resolution system. The present article generalizes the scheme initially introduced for a pure atomic liquid in slab geometry to more practically relevant situations involving (i) a molecular dipolar solvent (e.g., water); (ii) a radial geometry (i.e., spherical rather than planar layers); and (iii) the inclusion of a solute (e.g., water molecule, dipeptide, ion, or ion pair). [ABSTRACT FROM AUTHOR]

Replica-exchange enveloping distribution sampling (RE-EDS) is a pathway-independent multistate free-energy method currently implemented in the GROMOS software package for molecular dynamics (MD) simulations. It has a high intrinsic sampling efficiency as the interactions between the unperturbed particles have to be calculated only once for multiple end-states. As a result, RE-EDS is an attractive method for the calculation of relative solvation and binding free energies. An essential requirement for reaching this high efficiency is the separability of the nonbonded interactions into solute–solute, solute–environment, and environment–environment contributions. Such a partitioning is trivial when using a Coulomb term with a reaction-field (RF) correction to model the electrostatic interactions but not when using lattice-sum schemes. To avoid cutoff artifacts, the RF correction is typically used in combination with a charge-group-based cutoff, which is not supported by most small-molecule force fields as well as other MD engines. To address this issue, we investigate the combination of RE-EDS simulations with a recently introduced RF scheme including a shifting function that enables the rigorous calculation of RF electrostatics with atom-based cutoffs. The resulting approach is validated by calculating solvation free energies with the generalized AMBER force field in water and chloroform using both the GROMOS software package and a proof-of-concept implementation in OpenMM. [ABSTRACT FROM AUTHOR]

The calculation of a protein-ligand binding free energy based on molecular dynamics (MD) simulations generally relies on a thermodynamic cycle in which the ligand is alchemically inserted into the system, both in the solvated protein and free in solution. The corresponding ligand-insertion free energies are typically calculated in nanoscale computational boxes simulated under periodic boundary conditions and considering electrostatic interactions defined by a periodic lattice-sum. This is distinct from the ideal bulk situation of a system of macroscopic size simulated under non-periodic boundary conditions with Coulombic electrostatic interactions. This discrepancy results in finite-size effects, which affect primarily the charging component of the insertion free energy, are dependent on the box size, and can be large when the ligand bears a net charge, especially if the protein is charged as well. This article investigates finite-size effects on calculated charging free energies using as a test case the binding of the ligand 2-amino-5-methylthiazole (net charge +1 e) to a mutant form of yeast cytochrome c peroxidase in water. Considering different charge isoforms of the protein (net charges -5, 0, +3, or +9 e), either in the absence or the presence of neutralizing counter-ions, and sizes of the cubic computational box (edges ranging from 7.42 to 11.02 nm), the potentially large magnitude of finite-size effects on the raw charging free energies (up to 17.1 kJ mol(-1)) is demonstrated. Two correction schemes are then proposed to eliminate these effects, a numerical and an analytical one. Both schemes are based on a continuum-electrostatics analysis and require performing Poisson-Boltzmann (PB) calculations on the protein-ligand system. While the numerical scheme requires PB calculations under both non-periodic and periodic boundary conditions, the latter at the box size considered in the MD simulations, the analytical scheme only requires three non-periodic PB calculations for a given system, its dependence on the box size being analytical. The latter scheme also provides insight into the physical origin of the finite-size effects. These two schemes also encompass a correction for discrete solvent effects that persists even in the limit of infinite box sizes. Application of either scheme essentially eliminates the size dependence of the corrected charging free energies (maximal deviation of 1.5 kJ mol(-1)). Because it is simple to apply, the analytical correction scheme offers a general solution to the problem of finite-size effects in free-energy calculations involving charged solutes, as encountered in calculations concerning, e.g., protein-ligand binding, biomolecular association, residue mutation, pKa and redox potential estimation, substrate transformation, solvation, and solvent-solvent partitioning.

A new approach termed Adaptive Solvent-Scaling (AdSoS) is introduced for performing simulations of a solute embedded in a fine-grained (FG) solvent region itself surrounded by a coarse-grained (CG) solvent region, with a continuous FG ↔ CG switching of the solvent resolution across a buffer layer. Instead of relying on a distinct CG solvent model, the AdSoS scheme is based on CG models defined by a dimensional scaling of the FG solvent by a factor s, accompanied by an s-dependent modulation of the atomic masses and interaction parameters. The latter changes are designed to achieve an isomorphism between the dynamics of the FG and CG models, and to preserve the dispersive and dielectric solvation properties of the solvent with respect to a solute at FG resolution. This scaling approach offers a number of advantages compared to traditional coarse-graining: (i) the CG parameters are immediately related to those of the FG model (no need to parameterize a distinct CG model); (ii) nearly ideal mixing is expected for CG variants with similar s-values (ideal mixing holding in the limit of identical s-values); (iii) the solvent relaxation timescales should be preserved (no dynamical acceleration typical for coarse-graining); (iv) the graining level NG (number of FG molecules represented by one CG molecule) can be chosen arbitrarily (in particular, NG = s3 is not necessarily an integer); and (v) in an adaptive-resolution scheme, this level can be varied continuously as a function of the position (without requiring a bundling mechanism), and this variation occurs at a constant number of particles per molecule (no occurrence of fractional degrees of freedom in the buffer layer). By construction, the AdSoS scheme minimizes the thermodynamic mismatch between the different regions of the adaptive-resolution system, leading to a nearly homogeneous scaled solvent density s3ρ. Residual density artifacts in and at the surface of the boundary layer can easily be corrected by means of a grid-based biasing potential constructed in a preliminary pure-solvent simulation. This article introduces the AdSoS scheme and provides an initial application to pure atomic liquids (no solute) with Lennard-Jones plus Coulomb interactions in a slab geometry. [ABSTRACT FROM AUTHOR]

Over the past few decades, the experimental literature has consistently reported observations of attraction between like-charged colloidal particles and macromolecules in aqueous solution. Examples include nucleic acids and colloidal particles in the bulk solution and under confinement, and biological liquid–liquid phase separation. This observation is at odds with the intuitive expectation of an interparticle repulsion that decays monotonically with distance. Although attraction between like-charged particles can be rationalized theoretically in the strong-coupling regime, e.g., in the presence of multivalent counterions, recurring accounts of long-range attraction in aqueous solution containing monovalent ions at low ionic strength have posed an open conundrum. Here, we show that the behavior of molecular water at an interface—traditionally disregarded in the continuum electrostatics picture—provides a mechanism to explain the attraction between like-charged objects in a broad spectrum of experiments. This basic principle will have important ramifications in the ongoing quest to better understand intermolecular interactions in solution. [ABSTRACT FROM AUTHOR]

The absolute intrinsic hydration free energy G H + , w a t ◦ of the proton, the surface electric potential jump χ w a t ◦ upon entering bulk water, and the absolute redox potential V H + , w a t ◦ of the reference hydrogen electrode are cornerstone quantities for formulating single-ion thermodynamics on absolute scales. They can be easily calculated from each other but remain fundamentally elusive, i.e., they cannot be determined experimentally without invoking some extra-thermodynamic assumption (ETA). The Born model provides a natural framework to formulate such an assumption (Born ETA), as it automatically factors out the contribution of crossing the water surface from the hydration free energy. However, this model describes the short-range solvation inaccurately and relies on the choice of arbitrary ion-size parameters. In the present study, both shortcomings are alleviated by performing first-principle calculations of the hydration free energies of the sodium (Na+) and potassium (K+) ions. The calculations rely on thermodynamic integration based on quantum-mechanical molecular-mechanical (QM/MM) molecular dynamics (MD) simulations involving the ion and 2000 water molecules. The ion and its first hydration shell are described using a correlated ab initio method, namely resolution-of-identity second-order Møller-Plesset perturbation (RIMP2). The next hydration shells are described using the extended simple point charge water model (SPC/E). The hydration free energy is first calculated at the MM level and subsequently increased by a quantization term accounting for the transformation to a QM/MM description. It is also corrected for finite-size, approximate-electrostatics, and potential-summation errors, as well as standard-state definition. These computationally intensive simulations provide accurate first-principle estimates for G H + , w a t ◦ , χ w a t ◦ , and V H + , w a t ◦ , reported with statistical errors based on a confidence interval of 99%. The values obtained from the independent Na+ and K+ simulations are in excellent agreement. In particular, the difference between the two hydration free energies, which is not an elusive quantity, is 73.9 ± 5.4 kJ mol−1 (K+ minus Na+), to be compared with the experimental value of 71.7 ± 2.8 kJ mol−1. The calculated values of G H + , w a t ◦ , χ w a t ◦ , and V H + , w a t ◦ (−1096.7 ± 6.1 kJ mol−1, 0.10 ± 0.10 V, and 4.32 ± 0.06 V, respectively, averaging over the two ions) are also in remarkable agreement with the values recommended by Reif and Hünenberger based on a thorough analysis of the experimental literature (−1100 ± 5 kJ mol−1, 0.13 ± 0.10 V, and 4.28 ± 0.13 V, respectively). The QM/MM MD simulations are also shown to provide an accurate description of the hydration structure, dynamics, and energetics. [ABSTRACT FROM AUTHOR]

The CombiFF approach is a workflow for the automated refinement of force-field parameters against experimental condensed-phase data, considering entire classes of organic molecules constructed using a fragment library via combinatorial isomer enumeration. One peculiarity of this approach is that it relies on an electronegativity-equalization scheme to account for induction effects within molecules, with values of the atomic hardness and electronegativity as electrostatic parameters, rather than the partial charges themselves. In a previous article [M. P. Oliveira, M. Andrey, S. R. Rieder, L. Kern, D. F. Hahn, S. Riniker, B. A. C. Horta and P. H. Hu¨nenberger, J. Chem. Theory. Comput. 2020, 16, 7525], CombiFF was introduced and applied to calibrate a GROMOS-compatible united-atom force field for the saturated acyclic (halo-)alkane family. Here, this scheme is employed for the construction of a corresponding force field for saturated acyclic compounds encompassing eight common chemical functional groups involving oxygen and/or nitrogen atoms, namely: ether, aldehyde, ketone, ester, alcohol, carboxylic acid, amine, and amide. Monofunctional as well as homo-polyfunctional compounds are considered. A total of 1712 experimental liquid densities ρliq and vaporization enthalpies ΔHvap concerning 1175 molecules are used for the calibration (339 molecules) and validation (836 molecules) of the 102 non-bonded interaction parameters of the force field. Using initial parameter values based on the GROMOS 2016H66 parameter set, convergence is reached after five iterations. Given access to one processor per simulated system, this operation only requires a few days of wall-clock computing time. After optimization, the root-mean-square deviations from experiment are 29.9 (22.4) kg m-3 for ρliq and 4.1 (5.5) kJ mol-1 for ΔHvap for the calibration (validation) set. Thus, a very good level of agreement with experiment is achieved in terms of these two properties, although the errors are inhomogeneously distributed across the different chemical functional groups. [ABSTRACT FROM AUTHOR]

Estimating the relative stabilities of different conformational states of a (bio-)molecule using molecular dynamics simulations involves two challenging problems: the conceptual problem of how to define the states of interest and the technical problem of how to properly sample these states, along with achieving a sufficient number of interconversion transitions. In this study, the two issues are addressed in the context of a decaalanine peptide in water, by considering the 310-, α-, and π-helical states. The simulations rely on the ball-and-stick local-elevation umbrella-sampling (B&S-LEUS) method. In this scheme, the states are defined as hyperspheres (balls) in a (possibly high dimensional) collective-coordinate space and connected by hypercylinders (sticks) to ensure transitions. A new object, the pipe, is also introduced here to handle curvilinear pathways. Optimal sampling within the so-defined space is ensured by confinement and (one-dimensional) memory-based biasing potentials associated with the three different kinds of objects. The simulation results are then analysed in terms of free energies using reweighting, possibly relying on two distinct sets of collective coordinates for the state definition and analysis. The four possible choices considered for these sets are Cartesian coordinates, hydrogen-bond distances, backbone dihedral angles, or pairwise sums of successive backbone dihedral angles. The results concerning decaalanine underline that the concept of conformational state may be extremely ambiguous, and that its tentative absolute definition as a free-energy basin remains subordinated to the choice of a specific analysis space. For example, within the force-field employed and depending on the analysis coordinates selected, the 310-helical state may refer to weakly overlapping collections of conformations, differing by as much as 25 kJ mol-1 in terms of free energy. As another example, the π-helical state appears to correspond to a free-energy basin for three choices of analysis coordinates, but to be unstable with the fourth one. The problem of conformational-state definition may become even more intricate when comparison with experiment is involved, where the state definition relies on spectroscopic or functional observables. [ABSTRACT FROM AUTHOR]