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Computational Modelling of Biological Processes with Peptides and Proteins

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A special issue of Polymers (ISSN 2073-4360). This special issue belongs to the section "Polymer Physics and Theory".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 23301

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Special Issue Editor

Dr. Sergio Madurga

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Guest Editor

Department of Materials Science and Physical Chemistry & Research Institute of Theoretical and Computational Chemistry (IQTCUB) of Barcelona University (UB), 08028 Barcelona, Spain
Interests: molecular dynamics; Monte Carlo; reaction–diffusion processes; peptides; polyelectrolytes; constant pH simulations; conformational properties; charge regulation

Special Issue Information

Dear Colleagues,

This Special Issue focused on the current state-of-the-art of modeling of important biological phenomena of peptides and proteins, including protein folding/misfolding, aggregation, diffusion, and enzyme catalysis from all-atom to coarse-grained simulations.

Papers are sought that discuss the latest research in the area or summarize selected areas of the field. The scope of the Special Issue encompasses the modeling, simulation, and characterization of processes of peptides and proteins, especially with enhanced sampling methods such as replica-exchange molecular dynamics, metadynamics, simulated annealing, enhanced Monte Carlo methods or Brownian dynamics.

Of particular interest are the characterization of intrinsic disordered proteins (IDPs), the simulation of the effect of pH, and the importance of charge regulation in macromolecular interactions, diffusion, and recognition.

Prof. Sergio Madurga
Guest Editor

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Keywords

Molecular dynamics simulation
Enhanced sampling
Peptides
IDPs
Protein folding
Misfolding
Metadynamics
Replica-exchange molecular dynamics

Published Papers (7 papers)

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Research

21 pages, 5342 KiB

Open AccessEditor’s ChoiceArticle

Role of pK_A in Charge Regulation and Conformation of Various Peptide Sequences

by Raju Lunkad, Anastasiia Murmiliuk, Zdeněk Tošner, Miroslav Štěpánek and Peter Košovan

Polymers 2021, 13(2), 214; https://doi.org/10.3390/polym13020214 - 9 Jan 2021

Cited by 24 | Viewed by 3771

Abstract

Peptides containing amino acids with ionisable side chains represent a typical example of weak ampholytes, that is, molecules with multiple titratable acid and base groups, which generally exhibit charge regulating properties upon changes in pH. Charged groups on an ampholyte interact electrostatically with each other, and their interaction is coupled to conformation of the (macro)molecule, resulting in a complex feedback loop. Their charge-regulating properties are primarily determined by the

p K_{A}

of individual ionisable side-chains, modulated by electrostatic interactions between the charged groups. The latter is determined by the amino acid sequence in the peptide chain. In our previous work we introduced a simple coarse-grained model of a flexible peptide. We validated it against experiments, demonstrating its ability to quantitatively predict charge on various peptides in a broad range of pH. In the current work, we investigated two types of peptide sequences: diblock and alternating, each of them consisting of an equal number of amino acids with acid and base side-chains. We showed that changing the sequence while keeping the same overall composition has a profound effect on the conformation, whereas it practically does not affect total charge on the peptide. Nevertheless, the sequence significantly affects the charge state of individual groups, showing that the zero net effect on the total charge is a consequence of unexpected cancellation of effects. Furthermore, we investigated how the difference between the

p K_{A}

of acid and base side chains affects the charge and conformation of the peptide, showing that it is possible to tune the charge-regulating properties by following simple guiding principles based on the

p K_{A}

and on the amino acid sequence. Our current results provide a theoretical basis for understanding of the complex coupling between the ionisation and conformation in flexible polyampholytes, including synthetic polymers, biomimetic materials and biological molecules, such as intrinsically disordered proteins, whose function can be regulated by changes in the pH. Full article

(This article belongs to the Special Issue Computational Modelling of Biological Processes with Peptides and Proteins)

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Graphical abstract

9 pages, 1590 KiB

Open AccessArticle

Effect of the Water Model in Simulations of Protein–Protein Recognition and Association

by Agustí Emperador, Ramon Crehuet and Elvira Guàrdia

Polymers 2021, 13(2), 176; https://doi.org/10.3390/polym13020176 - 6 Jan 2021

Cited by 9 | Viewed by 2243

Abstract

We study self-association of ubiquitin and the disordered protein ACTR using the most commonly used water models. We find that dissociation events are found only with TIP4P-EW and TIP4P/2005, while the widely used TIP3P water model produces straightforward aggregation of the molecules due to the absence of dissociation events. We also find that TIP4P/2005 is the only water model that reproduces the fast association/dissociation dynamics of ubiquitin and best identifies its binding surface. Our results show the critical role of the water model in the description of protein–protein interactions and binding. Full article

(This article belongs to the Special Issue Computational Modelling of Biological Processes with Peptides and Proteins)

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Figure 1

14 pages, 779 KiB

Open AccessEditor’s ChoiceArticle

Protein Unfolding and Aggregation near a Hydrophobic Interface

by David March, Valentino Bianco and Giancarlo Franzese

Polymers 2021, 13(1), 156; https://doi.org/10.3390/polym13010156 - 3 Jan 2021

Cited by 26 | Viewed by 3955 | Correction

Abstract

The behavior of proteins near interfaces is relevant for biological and medical purposes. Previous results in bulk show that, when the protein concentration increases, the proteins unfold and, at higher concentrations, aggregate. Here, we study how the presence of a hydrophobic surface affects this course of events. To this goal, we use a coarse-grained model of proteins and study by simulations their folding and aggregation near an ideal hydrophobic surface in an aqueous environment by changing parameters such as temperature and hydrophobic strength, related, e.g., to ions concentration. We show that the hydrophobic surface, as well as the other parameters, affect both the protein unfolding and aggregation. We discuss the interpretation of these results and define future lines for further analysis, with their possible implications in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Computational Modelling of Biological Processes with Peptides and Proteins)

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Graphical abstract

20 pages, 6254 KiB

Open AccessFeature PaperArticle

On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

by Cristian Privat, Sergio Madurga, Francesc Mas and Jaime Rubio-Martínez

Polymers 2021, 13(1), 99; https://doi.org/10.3390/polym13010099 - 29 Dec 2020

Cited by 2 | Viewed by 3158

Abstract

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations. Full article

(This article belongs to the Special Issue Computational Modelling of Biological Processes with Peptides and Proteins)

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Graphical abstract

13 pages, 4944 KiB

Open AccessArticle

Effect of pH on the Supramolecular Structure of Helicobacter pylori Urease by Molecular Dynamics Simulations

by Haruna L. Barazorda-Ccahuana, Badhin Gómez, Francesc Mas and Sergio Madurga

Polymers 2020, 12(11), 2713; https://doi.org/10.3390/polym12112713 - 17 Nov 2020

Cited by 9 | Viewed by 2930

Abstract

The effect of pH on the supramolecular structure of Helicobacter pylori urease was studied by means of molecular dynamics simulations at seven different pHs. Appropriate urease charge distributions were calculated using a semi-grand canonical Monte Carlo (SGCMC) procedure that assigns each residue’s charge [...] Read more.

K_{a}

obtained by PROPKA. The effect of pH on protein stability has been analyzed through root-mean-square deviation (RMSD), radius of gyration (RG), solvent-accessible surface area (SASA), hydrogen bonds (HB) and salt bridges (SB). Urease catalyses the hydrolysis of urea in 12 active sites that are covered by mobile regions that act like flaps. The mobility of these flaps is increased at acidic pHs. However, extreme acidic conditions cause urease to have the least number of stabilizing interactions. This initiates the process of denaturalization, wherein the four

{(α β)}_{3}

subunits of the global structure ((

α β

)

_{3}

)

_{4}

of urease start to separate. Full article

(This article belongs to the Special Issue Computational Modelling of Biological Processes with Peptides and Proteins)

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Graphical abstract

15 pages, 3240 KiB

Open AccessArticle

Predicting Antibody Neutralization Efficacy in Hypermutated Epitopes Using Monte Carlo Simulations

by Pep Amengual-Rigo, Jorge Carrillo, Julià Blanco and Victor Guallar

Polymers 2020, 12(10), 2392; https://doi.org/10.3390/polym12102392 - 17 Oct 2020

Viewed by 3030

Abstract

Human Immunodeficiency Virus 1 (HIV-1) evades adaptive immunity by means of its extremely high mutation rate, which allows the HIV envelope glycoprotein to continuously escape from the action of antibodies. However, some broadly neutralizing antibodies (bNAbs) targeting specific viral regions show the ability to block the infectivity of a large number of viral variants. The discovery of these antibodies opens new avenues in anti-HIV therapy; however, they are still suboptimal tools as their amplitude of action ranges between 50% and 90% of viral variants. In this context, being able to discriminate between sensitive and resistant strains to an antibody would be of great interest for the design of optimal clinical antibody treatments and to engineer potent bNAbs for clinical use. Here, we describe a hierarchical procedure to predict the antibody neutralization efficacy of multiple viral isolates to three well-known anti-CD4bs bNAbs: VRC01, NIH45-46 and 3BNC117. Our method consists of simulating the three-dimensional binding process between the gp120 and the antibody by using Protein Energy Landscape Exploration (PELE), a Monte Carlo stochastic approach. Our results clearly indicate that the binding profiles of sensitive and resistant strains to a bNAb behave differently, showing the latter’s weaker binding profiles, that can be exploited for predicting antibody neutralization efficacy in hypermutated HIV-1 strains. Full article

(This article belongs to the Special Issue Computational Modelling of Biological Processes with Peptides and Proteins)

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Graphical abstract

13 pages, 20952 KiB

Open AccessArticle

Heat-Stable Hazelnut Profilin: Molecular Dynamics Simulations and Immunoinformatics Analysis

by Haruna L. Barazorda-Ccahuana, Vinicius Theiss-De-Rosso, Diego Ernesto Valencia and Badhin Gómez

Polymers 2020, 12(8), 1742; https://doi.org/10.3390/polym12081742 - 5 Aug 2020

Cited by 5 | Viewed by 3608

Abstract

Heat treatment can modify the allergenic potential, reducing allergenicity in specific proteins. Profilins are one of the important hazelnut allergens; these proteins are considered panallergens due to their high capacity for cross-reactivity with other allergens. In the present work, we evaluated the thermostability of hazelnut profilin, combining molecular dynamics simulation and immunoinformatic techniques. This approach helped us to have reliable results in immunogenicity studies. We modeled Cor a 2 profilin and applied annealing simulation, equilibrium, and production simulation at constant temperatures ranging from 300 to 500 K using Gromacs software. Despite the hazelnut profilins being able to withstand temperatures of up to 400 K, this does not seem to reduce its allergenicity. We have found that profilin subjected to temperatures of 450 and 500 K could generate cross-reactivity with other food allergens. In conclusion, we note a remarkable thermostability of Cor a 2 at 400 K which avoids its structural unfolding. Full article

(This article belongs to the Special Issue Computational Modelling of Biological Processes with Peptides and Proteins)

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