Specific Interactions of Sodium Salts with Alanine Dipeptide and Tetrapeptide in Water: Insights from Molecular Dynamics

We examine computationally the dipeptide and tetrapeptide of alanine in pure water and solutions of sodium chloride (NaCl) and iodide (NaI), with salt concentrations up to 3 M. Enhanced sampling of the configuration space is achieved by the replica exchange method. In agreement with other works, we observe preferential sodium interactions with the peptide carbonyl groups, which are enhanced in the NaI solutions due to the increased affinity of the less hydrophilic iodide anion for the peptide methyl side-chains and terminal blocking groups. These interactions have been associated with a decrease in the helicities of more complex peptides. In our simulations, both salts have a small effect on the dipeptide, but consistently stabilize the intramolecular hydrogen-bonding interactions and “α-helical” conformations of the tetrapeptide. This behavior, and an analysis of the intermolecular interaction energies show that ion–peptide interactions, or changes in the peptide hydration due to salts, are not sufficient determining factors of the peptide conformational preferences. Additional simulations suggest that the observed stabilizing effect is not due to the employed force-field, and that it is maintained in short peptides but is reversed in longer peptides. Thus, the peptide conformational preferences are determined by an interplay of energetic and entropic factors, arising from the peptide sequence and length and the composition of the solution

Helix Formation by Alanine-Based Peptides in Pure Water and Electrolyte Solutions: Insights from Molecular Dynamics Simulations

Specific ion effects on oligopeptide conformations in solution are attracting strong research attention, because of their impact on the protein-folding problem and on several important biological–biotechnological applications. In this work, we have addressed specific effects of electrolytes on the tendency of oligopeptides toward formation and propagation of helical segments. We have used replica-exchange molecular dynamics (REMD) simulations to study the conformations of two short hydrophobic peptides [Ace-(AAQAA)₃-Nme (AQ), and Ace-A₈-Nme (A8)] in pure water and in aqueous solutions of sodium chloride (NaCl) and sodium iodide (NaI) with concentrations of 1 and 3 M. The average helicities of the AQ peptide have been analyzed to yield Lifson–Roig (LR) parameters for helix nucleation and helix propagation. The salt dependence of these parameters suggests that electrolytes tend to stabilize the helical conformations of short peptides by enhancing the <i>helix nucleation</i> parameter. The helical conformations of longer oligopeptides are destabilized in the presence of salts, however, because the <i>helix propagation</i> parameters are reduced by electrolytes. On top of this general trend, we observe a significant specific salt effect in these simulations. The hydrophobic iodide ion in NaI solutions has a high affinity for the peptide backbone, which reflects itself in an enhanced helix nucleation and a reduced helix propagation parameter with respect to pure water or NaCl solutions. The present work thus explains the computational evidence that electrolytes tend to stabilize the compact conformations of short peptides and destabilize them for longer peptides, and it also sheds additional light on the specific salt effects on compact peptide conformations

Predicting the Acid/Base Behavior of Proteins: A Constant-pH Monte Carlo Approach with Generalized Born Solvent

The acid/base properties of proteins are essential in biochemistry, and proton binding is a valuable reporter on electrostatic interactions. We propose a constant-pH Monte Carlo strategy to compute protonation free energies and pKa’s. The solvent is described implicitly, through a generalized Born model. The electronic polarizability and backbone motions of the protein are included through the protein dielectric constant. Side chain motions are described explicitly, by the Monte Carlo scheme. An efficient computational algorithm is described, which allows us to treat the fluctuating shape of the protein/solvent boundary in a way that is numerically exact (within the GB framework); this contrasts with several previous constant-pH approaches. For a test set of six proteins and 78 titratable groups, the model performs well, with an rms error of 1.2 pH units. While this is slightly greater than a simple Null model (rms error of 1.1) and a fully empirical model (rms error of 0.9), it is obtained using physically meaningful model parameters, including a low protein dielectric of four. Importantly, similar performance is obtained for side chains with large and small pKa shifts (relative to a standard model compound). The titration curve slopes and the conformations sampled are reasonable. Several directions to improve the method further are discussed

Toward Rational Design of Selective Molecularly Imprinted Polymers (MIPs) for Proteins: Computational and Experimental Studies of Acrylamide Based Polymers for Myoglobin

Molecularly imprinted polymers (MIPs) have potential as alternatives to antibodies in the diagnosis and treatment of disease. However, atomistic level knowledge of the prepolymerization process is limited that would facilitate rational design of more efficient MIPs. Accordingly, we have investigated using computation and experiment the protein–monomer binding interactions that may influence the desired specificity. Myoglobin was used as the target protein and five different acrylamide-based monomers were considered. Protein binding sites were predicted using SiteMap and binding free energies of monomers at each site were calculated using MM-GBSA. Statistical thermodynamic analysis and study of atomistic interactions facilitated rationalization of monomer performance in MIP rebinding studies (% rebind; imprinting factors). CD spectroscopy was used to determine monomer effects on myoglobin secondary structure, with all monomers except the smallest monomer (acrylamide) causing significant changes. A complex interplay between different protein–monomer binding effects and MIP efficacy was observed. Validation of hypotheses for key binding features was achieved by rational selection of two different comonomer MIP combinations that produced experimental results in agreement with predictions. The comonomer studies revealed that uniform, noncompetitive binding of monomers around a target protein is favorable. This study represents a step toward future rational in silico design of MIPs for proteins

Self-Assembly of an Aspartate-Rich Sequence from the Adenovirus Fiber Shaft: Insights from Molecular Dynamics Simulations and Experiments

The self-assembly of short peptides into fibrous nanostructures (such as fibrils and tubes) has recently become the subject of intense theoretical and experimental scrutiny, as such assemblies are promising candidates for nanobiotechnological applications. The sequences of natural fibrous proteins may provide a rich source of inspiration for the design of such short self-assembling peptides. We describe the self-assembly of the aspartate-rich undecapeptide (NH₃⁺-LSG­SDS­DTL­TV-NH₂), a sequence derived from the shaft of the adenovirus fiber. We demonstrate that the peptide assembles experimentally into amyloid-type fibrils according to widely accepted diagnostic criteria. In addition, we investigate an aqueous solution of undecapeptides by molecular dynamics simulations with an implicit (GB) solvent model. The peptides are frequently arranged in intermolecular β-sheets, in line with their amyloidogenic propensity. On the basis of both experimental and theoretical insights, we suggest possible structural models of the fibrils and their potential use as scaffolds for templating of inorganic materials