While most force field efforts in biomolecular simulation have focused on the parametrization of the protein, relatively little attention has been paid to the quality of the accompanying solvent model. These considerations are especially relevant for simulations of intrinsically disordered peptides and proteins, for which energy differences between conformations are small and interactions with water are enhanced. In this work, we investigate the accuracy of the AMBER ff99SB force field when combined with the standard TIP3P model or the more recent TIP4P-Ew water model, to generate conformational ensembles for disordered trialanine (Ala3), triglycine (Gly3), and trivaline (Val3) peptides. We find that the TIP4P-Ew water model yields significantly better agreement with experimentally measured scalar couplings-and therefore more accurate conformational ensembles-for both Ala3 and Gly3. For Val3, however, we find that the TIP3P and TIP4P-Ew ensembles are equivalent in their performance. To further improve the protein-water force field combination and obtain more accurate intrinsic conformational preferences, we derive a straightforward perturbation to the ϕ' backbone dihedral potential that shifts the β-PPII equilibrium. We find that the revised ϕ' backbone dihedral potential yields improved conformational ensembles for a variety of small peptides and maintains the stability of the globular ubiquitin protein in TIP4P-Ew water.

Biomolecular force field development has been instrumental in improving the predictive power of molecular simulations over the past four decades. More recently, the era of large quantitative experimental datasets and ubiquitous high performance computing power has enabled rapid progress in the field. In this review we summarize recent developments in all-atom protein, nucleic acid, and small molecule force fields, paying specific attention to developments in parameterization methods and improvements in the representations of nonbonded interactions that are critical for solving the challenging biophysical problems of the present. We also sketch out new avenues for force field development and grand challenge applications for the near future.

Using a coarse-grained lipid and peptide model, we show that the free energy stabilization of amyloid-β in heterogeneous lipid membranes is predicted to have a dependence on asymmetric distributions of cholesterol compositions across the membrane leaflets. We find that a highly asymmetric cholesterol distribution that is depleted on the exofacial leaflet but enhanced on the cytofacial leaflet of the model lipid membrane thermodynamically favors membrane retention of a fully embedded Aβ peptide. However, in the case of cholesterol redistribution that increases concentration of cholesterol on the exofacial layer, typical of aging or Alzheimer's disease, the free energy favors peptide extrusion of the highly reactive N-terminus into the extracellular space that may be vulnerable to aggregation, oligomerization, or deleterious oxidative reactivity.

Vasopressin and oxytocin are intrinsically disordered cyclic nonapeptides belonging to a family of neurohypophysial hormones. Although unique in their functions, these peptides differ only by two residues and both feature a tocin ring formed by the disulfide bridge between first and sixth cysteine residues. This sequence and structural similarity are experimentally linked to oxytocin agonism at vasopressin receptors and vasopressin antagonism at oxytocin receptors. Yet single- or double-residue mutations in both peptides have been shown to have drastic impacts on their activities at either receptor, and possibly the ability to bind to their neurophysin carrier protein. In this study we perform molecular dynamics simulations of the unbound native and mutant sequences of the oxytocin and vasopressin hormones to characterize their structural ensembles. We classify the subpopulations of these structural ensembles on the basis of the distributions of radius of gyration and secondary structure and hydrogen-bonding features of the canonical tocin ring and disordered tail region. We then relate the structural changes observed in the unbound form of the different hormone sequences to experimental information about peptide receptor binding, and more indirectly, carrier protein binding affinity, receptor activity, and protease degradation. This study supports the hypothesis that the structural characteristics of the unbound form of an IDP can be used to predict structural or functional preferences of its functional bound form.

Phosphorylation of select amino acid residues is one of the most common biological mechanisms for regulating protein structures and functions. While computational modeling can be used to explore the detailed structural changes associated with phosphorylation, most molecular mechanics force fields developed for the simulation of phosphoproteins have been noted to be inconsistent with experimental data. In this work, we parameterize force fields for the phosphorylated forms of the amino acids serine, threonine, and tyrosine using the ForceBalance software package with the goal of improving agreement with experiments for these residues. Our optimized force field, denoted as FB18, is parameterized using high-quality ab initio potential energy scans and is designed to be fully compatible with the AMBER-FB15 protein force field. When utilized in MD simulations together with the TIP3P-FB water model, we find that FB18 consistently enhances the prediction of experimental quantities such as ³J NMR couplings and intramolecular hydrogen-bonding propensities in comparison to previously published models. As was reported with AMBER-FB15, we also see improved agreement with the reference QM calculations in regions at and away from local minima. We thus believe that the FB18 parameter set provides a promising route for the further investigation of the varied effects of protein phosphorylation.

An accurate representation of solute-water interactions is necessary for molecular dynamics simulations of biomolecules that reside in aqueous environments. Modern force fields and advanced water models describe solute-solute and water-water interactions reasonably accurately but have known shortcomings in describing solute-water interactions, demonstrated by the large differences between calculated and experimental solvation free energies across a range of peptide and drug chemistries. In this work, we introduce a method for optimizing solute-water van der Waals interactions to reproduce experimental solvation free energy data and apply it to the optimization of a fixed charge force field (AMBER ff99SB/GAFF) and advanced water model (TIP4P-Ew). We show that, with these optimizations, the combination of AMBER ff99SB/GAFF and TIP4P-Ew is able to reproduce the solvation free energies of a variety of biologically relevant small molecules to within 1.0 k(B)T. We further validate these optimizations by examining the aggregation propensities of dipeptide-water solutions, the conformational preferences of short disordered peptides, and the native state stability and dynamics of a folded protein.

The interplay of modern molecular simulation and high-quality nuclear magnetic resonance (NMR) experiments has reached a fruitful stage for quantitative characterization of structural ensembles of disordered peptides. Amyloid-β 1-42 (Aβ42), the primary peptide associated with Alzheimer's disease, and fragments such as Aβ21-30 are both classified as intrinsically disordered peptides (IDPs). We use a variety of NMR observables to validate de novo molecular dynamics simulations in explicit water to characterize the tertiary structure ensemble of Aβ42 and Aβ21-30 from the perspective of their classification as IDPs. Unlike the Aβ21-30 fragment that conforms to expectations of an IDP that is primarily extended, we find that Aβ42 samples conformations reflecting all possible secondary structure categories and spans the range of IDP classifications from collapsed structured states to highly extended conformations, making it an IDP with a far more heterogeneous tertiary ensemble.

The restrained electrostatic potential (RESP) approach is a highly regarded and widely used method of assigning partial charges to molecules for simulations. RESP uses a quantum-mechanical method that yields fortuitous overpolarization and thereby accounts only approximately for self-polarization of molecules in the condensed phase. Here we present RESP2, a next generation of this approach, where the polarity of the charges is tuned by a parameter, δ, which scales the contributions from gas- and aqueous-phase calculations. When the complete non-bonded force field model, including Lennard-Jones parameters, is optimized to liquid properties, improved accuracy is achieved, even with this reduced set of five Lennard-Jones types. We argue that RESP2 with δ≈0.6 (60% aqueous, 40% gas-phase charges) is an accurate and robust method of generating partial charges, and that a small set of Lennard-Jones types is good starting point for a systematic re-optimization of this important non-bonded term.