Influence of pH and sequence in peptide aggregation via molecular simulation

We employ a recently developed coarse-grained model for peptides and proteins where the effect of pH is automatically included. We explore the effect of pH in the aggregation process of the amyloidogenic peptide KTVIIE and two related sequences, using three different pH environments. Simulations using large systems (24 peptides chains per box) allow us to correctly account for the formation of realistic peptide aggregates. We evaluate the thermodynamic and kinetic implications of changes in sequence and pH upon peptide aggregation, and we discuss how a minimalistic coarse-grained model can account for these details.Comment: 21 pages, 4 figure

pH-dependent coarse-grained model of peptides

We propose the first, to our knowledge, coarse-grained modeling strategy for peptides where the effect of changes of the pH can be efficiently described. The idea is based on modeling the effects of the pH value on the main driving interactions. We use reference data from atomistic simulations and experimental databases and transfer its main physical features to the coarse-grained resolution according the principle of "consistency across the scales". The coarse-grained model is refined by finding a set of parameters that, when applied to peptides with different sequences and experimental properties, reproduces the experimental and atomistic data of reference. We use the such parameterized model for performing several numerical tests to check its transferability to other systems and to prove the universality of the related modeling strategy. We have tried systems with rather different response to pH variations, showing a highly satisfactory performance of the model.Comment: accepted for publication in Soft Matte

Improvement of Structure-Based Potentials for Protein Folding by Native and Nonnative Hydrogen Bonds

Pure Go models (where every native interaction equally stabilizes the folded state) have widely proved their convenience in the computational investigation of protein folding. However, a chemistry-based description of the real interactions also provides a desirable tune in the analysis of the folding process, and thus some hybrid Go potentials that combine both aspects have been proposed. Among all the noncovalent interactions that contribute to protein folding, hydrogen bonds are the only ones with a partial covalent character. This feature makes them directional and, thus, more difficult to model as part of the coarse-grained descriptions that are typically employed in Go models. Thanks to a simplified but rigorous representation of backbone hydrogen bonds that we have recently proposed, we present in this article a combined potential (Go + backbone hydrogen bond) to study the thermodynamics of protein folding in the frame of very simple simulation models. We show that the explicit inclusion of hydrogen bonds leads to a systematic improvement in the description of protein folding. We discuss a representative set of examples (from two-state folders to downhill proteins, with different types of native structures) that reveal a relevant agreement with experimental data

Simple model for the simulation of peptide folding and aggregation with different sequences

We present a coarse-grained interaction potential that, using just one single interaction bead per amino acid and only realistic interactions, can reproduce the most representative features of peptide folding. We combine a simple hydrogen bond potential, recently developed in our group, with a reduced alphabet for the amino acid sequence, which takes into account hydrophobic interactions. The sequence does not pose any additional influence in the torsional properties of the chain, as it often appears in previously published work. Our model is studied in equilibrium simulations at different temperatures and concentrations. At low concentrations the effect of hydrophobic interactions is determinant, as α-helices (isolated or in bundles) or β-sheets are the most populated conformations, depending on the simulated sequence. On the other hand, an increase in concentration translates into a higher influence of the hydrogen bond interactions, which mostly favor the formation of β-type aggregates, in agreement with experimental observations. These aggregates, however, still keep some distinct characteristics for different sequences

Sketching protein aggregation with a physics-based toy model

We explore the applicability of a single-bead coarse-grained molecular model to describe the competition between protein folding and aggregation. We have designed very simple and regular sequences, based on our previous studies on peptide aggregation, that successfully fold into the three main protein structural families (all-α, all-β, and α + β). Thanks to equilibrium computer simulations, we evaluate how temperature and concentration promote aggregation. Aggregates have been obtained for all the amino acid sequences considered, showing that this process is common to all proteins, as previously stated. However, each structural family presents particular characteristics that can be related to its specific balance between hydrogen bond and hydrophobic interactions. The model is very simple and has limitations, yet it is able to reproduce both the cooperative folding of isolated polypeptide chains with regular sequences and the formation of different types of aggregates at high concentrations

pH-dependent Response of Coiled Coils: A Coarse-Grained Molecular Simulation Study

In a recent work we proposed a coarse-grained methodology for studying the response of peptides when simulated at different values of pH; in this work we extend the methodology to analyze the pH-dependent behavior of coiled coils. This protein structure presents a remarkable chain stiffness andis formed by two or more long helical peptides that are interacting like the strands of a rope. Chain length and rigidity are the key aspects needed to extend previous peptide interaction potentials to this particular case; however the original model is naturally recovered when the length or the ridigity of the simulated chain are reduced. We apply the model and discuss results for two cases: (a) the folding/unfolding transition of a generic coiled coil as a function of pH; (b) behavior of a specific sequence as a function of the acidity conditions. In this latter case results are compared with experimental data from the literature in order to comment about the consistency of our approach

Modelos de interacción de enlace de hidrógeno para la simulación del plegamiento y la agregación de proteínas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Física I, leída el 06-02-2012Fac. de Ciencias QuímicasTRUEunpu

A refined hydrogen bond potential for flexible protein models

One of the major disadvantages of coarse-grained hydrogen bond potentials, for their use in protein folding simulations, is the appearance of abnormal structures when these potentials are used in flexible chain models, and no other geometrical restrictions or energetic contributions are defined into the system.We have efficiently overcome this problem, for chains of adequate size in a relevant temperature range, with a refined coarse-grained hydrogen bond potential. With it, we have been able to obtain nativelike alpha-helices and beta-sheets in peptidic systems, and successfully reproduced the competition between the populations of these secondary structure elements by the effect of temperature and concentration changes. In this manuscript we detail the design of the interaction potential and thoroughly examine its applicability in energetic and structural terms, considering factors such as chain length, concentration, and temperature