The AGBNP2 implicit solvent model, an evolution of the Analytical Generalized Born plus Non-Polar (AGBNP) model we have previously reported, is presented with the aim of modeling hydration effects beyond those described by conventional continuum dielectric representations. A new empirical hydration free energy component based on a procedure to locate and score hydration sites on the solute surface is introduced to model first solvation shell effects, such as hydrogen bonding, which are poorly described by continuum dielectric models. This new component is added to the Generalized Born and non-polar AGBNP models which have been improved with respect to the description of the solute volume description. We have introduced an analytical Solvent Excluding Volume (SEV) model which reduces the effect of spurious high-dielectric interstitial spaces present in conventional van der Waals representations of the solute volume. The AGBNP2 model is parametrized and tested with respect to experimental hydration free energies of small molecules and the results of explicit solvent simulations. Modeling the granularity of water is one of the main design principles employed for the the first shell solvation function and the SEV model, by requiring that water locations have a minimum available volume based on the size of a water molecule. We show that the new volumetric model produces Born radii and surface areas in good agreement with accurate numerical evaluations. The results of Molecular Dynamics simulations of a series of mini-proteins show that the new model produces conformational ensembles in substantially better agreement with reference explicit solvent ensembles than the original AGBNP model with respect to both structural and energetics measures.
Deep Dive into The AGBNP2 Implicit Solvation Model.
The AGBNP2 implicit solvent model, an evolution of the Analytical Generalized Born plus Non-Polar (AGBNP) model we have previously reported, is presented with the aim of modeling hydration effects beyond those described by conventional continuum dielectric representations. A new empirical hydration free energy component based on a procedure to locate and score hydration sites on the solute surface is introduced to model first solvation shell effects, such as hydrogen bonding, which are poorly described by continuum dielectric models. This new component is added to the Generalized Born and non-polar AGBNP models which have been improved with respect to the description of the solute volume description. We have introduced an analytical Solvent Excluding Volume (SEV) model which reduces the effect of spurious high-dielectric interstitial spaces present in conventional van der Waals representations of the solute volume. The AGBNP2 model is parametrized and tested with respect to experimenta
Water plays a fundamental role in virtually all biological processes. The accurate modeling of hydration thermodynamics is therefore essential for studying protein conformational equilibria, aggregation, and binding. Explicit solvent models arguably provide the most detailed and complete description of hydration phenomena. 1 They are, however, computationally demanding not only because of the large number of solvent atoms involved, but also because of the need to average over many solvent configurations to obtain meaningful thermodynamic data. Implicit solvent models, 2 which are based on the statistical mechanics concept of the solvent potential of mean force, 3 have been shown to be useful alternatives to explicit solvation for applications including protein folding and binding, 4 and small molecule hydration free energy prediction. 5 Modern implicit solvent models 6,7 include distinct estimators for the non-polar and electrostatic components of the hydration free energy. The non-polar component corresponds to the free energy of hydration of the uncharged solute while the electrostatic component corresponds to the free energy of turning on the solute partial charges. The latter is typically modeled treating the water solvent as a uniform high-dielectric continuum. 8 Methods based on the numerical solution of the Poisson-Boltzmann (PB) equation 9 provide a virtually exact representation of the response of the solvent within the dielectric continuum approximation. Recent advances extending dielectric continuum approaches have focused on the development of Generalized Born (GB) models, 10 which have been shown to reproduce with good accuracy PB and explicit solvent 7,11 results at a fraction of the computational expense. The development of computationally efficient analytical and differentiable GB methods based on pairwise descreening schemes 6,12,13 has made possible the integration of GB models in molecular dynamics packages for biological simulations. 14,15,16 The non-polar hydration free energy component accounts for all non-electrostatic solutesolvent interactions as well as hydrophobic interactions, 17 which are essential driving forces in biological processes such as protein folding 18,19,20,21 and binding. 22,23,24,25 Historically the non-polar hydration free energy has been modeled by empirical surface area models 26 which are still widely employed. 10,27,28,29,30,31,32,33,34,35 Surface area models are useful as a first approximation, however qualitative deficiencies have been observed. 29,36,37,38,39,40,41 Few years ago we presented the Analytical Generalized Born plus Non-Polar (AGBNP) implicit solvent model, 42 which introduced two key innovations with respect to both the electrostatic and non-polar components. Unlike most implicit solvent models, the AGBNP non-polar hydration free energy model includes distinct estimators for the solute-solvent van der Waals dispersion energy and cavity formation work components. The main advantages of a model based on the cavity/dispersion decomposition of the non-polar solvation free energy stem from its ability to describe both medium range solute-solvent dispersion interactions, which depend on solute composition, as well as conformational equilibria dominated by short-range hydrophobic interactions, which mainly depend on solute conformation alone. 40 A series of studies highlight the importance of the balance between hydrophobicity and dispersion interactions in regulating the structure of the hydration shell and the strength of interactions between macromolecules. 43,44,45 In AGBNP the work of cavity formation is described by a surface area-dependent model, 37,46,47,48 while the dispersion estimator is based on the integral of van der Waals solute-solvent interactions over the solvent modeled as a uniform continuum. 38 This form of the non-polar estimator had been motivated by a series of earlier studies 5,37,49,50,51,52 and has since been shown by us 38,53,54,55 and others 39,40,41,56 to be qualitatively superior to models based only on the surface area in reproducing explicit solvent results as well as rationalizing structural and thermodynamical experimental observations. The electrostatic solvation model in AGBNP is based on the pairwise descreening GB scheme 13 whereby the Born radius of each atom is obtained by summing an appropriate descreening function over its neighbors. The main distinction between the AGBNP GB model and conventional pairwise descreening implementations is that in AGBNP the volume scaling factors, which offset the overcounting of regions of space occupied by more than one atom, are computed from the geometry of the molecule rather than being introduced as geometryindependent parameters fit to either experiments or to numerical Poisson-Boltzmann results. 14,57,58,59 The reduction of number of parameters achieved with this strategy improves the transferability of the model to unusual functional groups often found in ligand molecul
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