The future of molecular dynamics simulations in drug discovery

Molecular dynamics simulations can now track rapid processes—those occurring in less than about a millisecond—at atomic resolution for many biologically relevant systems. These simulations appear poised to exert a significant impact on how new drugs are found, perhaps even transforming the very process of drug discovery. We predict here future results we can expect from, and enhancements we need to make in, molecular dynamics simulations over the coming 25 years, and in so doing set out several Grand Challenges for the field. In the context of the problems now facing the pharmaceutical industry, we ask how we can best address drug discovery needs of the next quarter century using molecular dynamics simulations, and we suggest some possible approaches

Mechanisms for the inhibition of amyloid aggregation by small ligands

The formation of amyloid aggregates is the hallmark of systemic and neurodegenerative disorders, also known as amyloidoses. Many proteins have been found to aggregate into amyloid-like fibrils and this process is recognized as a general tendency of polypeptides. Lysozyme, an antibacterial protein, is a well-studied model since it is associated in human with systemic amyloidosis and that is widely available from chicken eggs (HEWL, hen egg white lysozyme). In the present study we investigated the mechanism of interaction of aggregating HEWL with rosmarinic acid and resveratrol, that we verified to be effective and ineffective, respectively, in inhibiting aggregate formation. We used a multidisciplinary strategy to characterize such effects, combining biochemical and biophysical methods with molecular dynamics (MD) simulations on the HEWL peptide 49–64 to gain insights into the mechanisms and energy variations associated to amyloid formation and inhibition. MD revealed that neither resveratrol nor rosmarinic acid were able to compete with the initial formation of the β-sheet structure. We then tested the association of two β-sheets, representing the model of an amyloid core structure. MD showed that rosmarinic acid displayed an interaction energy and a contact map comparable to that of sheet pairings. On the contrary, resveratrol association energy was found to be much lower and its contact map largely different than that of sheet pairings. The overall characterization elucidated a possible mechanism explaining why, in this model, resveratrol is inactive in blocking fibril formation, whereas rosmarinic acid is instead a powerful inhibitor

Differential Electrostatic Interaction Patterns in SARS-CoV-1 and SARS-CoV-2 variants: A Molecular Dynamics Simulation Study

The SARS-related coronavirus (SARS-rCoV) is a highly contagious virus that has raised significant worldwide health concerns. It caused outbreaks in 2002-2003 and more recently in 2019-2020 with SARS-CoV-2. SARS-CoV-2 is responsible for the COVID-19 pandemic, which has resulted in a significant global impact on health and the economy. The spike protein of the virus plays a critical role in its infectivity and transmission, and the receptor-binding domain (RBD) within the spike protein is of particular interest, as it is responsible for binding to the human angiotensin-converting enzyme 2 (ACE2) receptor. In this study, we used Molecular dynamics (MD) simulations to investigate the electrostatic interaction patterns in the active and inactive models of SARS-CoV-1, SARS-CoV-2, and several variants of SARS-CoV-2, including the Alpha, Beta, Delta, and Epsilon variants. MD simulations are a computational method that allows us to model the motion of atoms and molecules over time, providing insights into the structure and behavior of biological molecules. The findings indicate differential electrostatic interaction patterns between the RBD of SARS-CoV-1 and SARS-CoV-2 spike protein. The RBD of SARS-CoV-2 exhibited a slower conformational pattern, which could influence higher stability, potentially affecting its binding affinity with the ACE2 receptor. Additionally, the Delta variant demonstrated significant differences in electrostatic interactions compared to the original SARS-CoV-2 strain, particularly in the N-terminal domain (NTD) and RBD regions. These findings suggest that Delta variant mutations could affect the RBD’s binding affinity to the ACE2 receptor, impacting transmission and virulence. Overall, this study highlights electrostatic interaction patterns in SARS-CoV-1, SARS-CoV-2, and variants, with implications for the development of long-term effective vaccines and therapeutics. Understanding the spike protein’s molecular basis may enable designing more effective treatments and strategies to prevent the spread of these viruses

Integrating Protein Dynamics And Enhanced Conformational Ensembles To Better Understand Their Role In Biomolecular Function

Proteins have been termed the building blocks of life due to their involvement in practically every biological process that occurs in a living organism. For years now, researchers have sought to uncover the underlying mechanisms employed by biomolecules to carry out such tasks and functions. Initial understanding of proteins and how they function, at the atomic level, was revolutionized by the generation of numerous average static structures via X-ray crystallographic methods. Nevertheless, although one or multiple three-dimensional structures exist for many proteins, biological activity cannot be solely explained by relatively rigid structures. Proteins are dynamic entities governed by their dynamic personalities where biological function is rooted in their internal motions, fluctuations, and conformational changes. However, despite many experimental and computational efforts, how protein motions or dynamics couple protein function remains poorly understood. Here, in this work, we employ standard molecular dynamics (MD) simulations and enhanced sampling methods (Rotatable accelerated MD-dual boost (RaMD-db)) to try and capture a more accurate representation of the dynamic nature of two enzymes, cyclophilin A and choline oxidase. We show that molecular dynamics is a powerful method and is more than capable of acquiring a more accurate representation of the dynamic nature of the enzymes, in comparison to experimental techniques. More so, RaMD-db, because it was able to sample conformational states that were never observed in standard MD. Furthermore, we showed, at an atomic level, how protein motions facilitate and are coupled to biological function in both cyclophilin A (CypA) and choline oxidase. Ultimately, an atomic level description of how protein motions facilitate function, provided by the results in this work, can be utilized for drug design advancement, protein engineering, and to gain a better understanding of protein participation in disease

Differential Electrostatic Interaction Patterns in SARS-CoV-1 and SARS-CoV-2 variants: A Molecular Dynamics Simulation Study

The SARS-related coronavirus (SARS-rCoV) is a highly contagious virus that has raised significant worldwide health concerns. It caused outbreaks in 2002-2003 and more recently in 2019-2020 with SARS-CoV-2. SARS-CoV-2 is responsible for the COVID-19 pandemic, which has resulted in a significant global impact on health and the economy. The spike protein of the virus plays a critical role in its infectivity and transmission, and the receptor-binding domain (RBD) within the spike protein is of particular interest, as it is responsible for binding to the human angiotensin-converting enzyme 2 (ACE2) receptor. In this study, we used Molecular dynamics (MD) simulations to investigate the electrostatic interaction patterns in the active and inactive models of SARS-CoV-1, SARS-CoV-2, and several variants of SARS-CoV-2, including the Alpha, Beta, Delta, and Epsilon variants. MD simulations are a computational method that allows us to model the motion of atoms and molecules over time, providing insights into the structure and behavior of biological molecules. The findings indicate differential electrostatic interaction patterns between the RBD of SARS-CoV-1 and SARS-CoV-2 spike protein. The RBD of SARS-CoV-2 exhibited a slower conformational pattern, which could influence higher stability, potentially affecting its binding affinity with the ACE2 receptor. Additionally, the Delta variant demonstrated significant differences in electrostatic interactions compared to the original SARS-CoV-2 strain, particularly in the N-terminal domain (NTD) and RBD regions. These findings suggest that Delta variant mutations could affect the RBD’s binding affinity to the ACE2 receptor, impacting transmission and virulence. Overall, this study highlights electrostatic interaction patterns in SARS-CoV-1, SARS-CoV-2, and variants, with implications for the development of long-term effective vaccines and therapeutics. Understanding the spike protein’s molecular basis may enable designing more effective treatments and strategies to prevent the spread of these viruses

Estudo de partição de biomoléculas em sistemas anfífilicos: desenvolvimento de uma estratégia recorrendo a dinâmica molecular

Amphiphilic molecules are interesting building blocks of self-assembled structures for a variety of biotechnological purposes, due to their hydrophobic and hydrophilic moieties. Some of them are deemed as biocompatible, capable of carrying biomolecules, while being highly tuneable and controlled with external cues. Such properties are advantageous in drug delivery applications. Ionic liquids have gained relevance since their discovery as not only responsive and adjustable, but also as promising alternatives to conventionally used solvents. This project aims to use molecular dynamics to the study of ammonium-based ionic liquids in the extraction and delivery of biomolecules, specifically gallic acid and ibuprofen. A multiscale strategy was followed to simulate systems using the GROMACS package for classical molecular dynamics simulations. High-resolution descriptions were used to create a novel coarse-grained model to reproduce the phase behaviour and partition studies. The partition of gallic acid and ibuprofen in the studied ionic liquid solutions was assessed, as well as the particular orientation of the biomolecule in the supramolecular structure of the ionic liquids, as well as the interactions generating each outcome. A pH-driven effect was verified as the main parameter affecting the studied systems. This work has the potential to pave the way for a transferable, transversal platform to analyse and test different biomolecule-IL combinations in aqueous solutions in order to save time and experimental resources in diverse applications.As moléculas anfifílicas são elementos de elevado potencial de estruturas auto-organizadas para vários fins biotecnológicos, devido às suas componentes hidrofóbica e hidrofílica. Parte destas são biocompatíveis, capazes de transportar biomoléculas e altamente ajustáveis e controláveis por fatores externos. Estas propriedades são particularmente relevantes em aplicações de libertação controlada de fármacos. Os líquidos iónicos são cada vez mais utilizados desde a descoberta da sua sensibilidade a estímulos, ajustabilidade e possível uso como alternativas sustentáveis a solventes convencionais. Este trabalho teve como objetivo utilizar dinâmica molecular para estudar líquidos iónicos à base de iões amónio para extração e libertação de biomoléculas, particularmente ácido gálico ou ibuprofeno. Foi utilizada uma estratégia de simulação em várias escalas com o pacote de simulação em dinâmica molecular clássica GROMACS, onde modelos com alta resolução foram usados para criar modelos de grão-grosso novos, mais eficientes em estudos de partição e comportamento de fases. Foi averiguada a partição de ácido gálico e ibuprofeno nas soluções de líquido iónico em questão, bem como a orientação da biomolécula na estrutura supramolecular do líquido iónico e as interações que levaram à mesma. Foi verificado um efeito à base do pH como o principal fator a afetar os sistemas estudados. Este trabalho tem o potencial de dar origem a uma plataforma transversal e transferível para analisar e testar várias combinações de biomoléculas e líquidos iónicos em soluções aquosas de forma a poupar tempo e recursos experimentais em diversas aplicações.Mestrado em Biotecnologi