CANCER, INFECTION AND AGING
Three vertices of a triangleDiseases that a priori can seem totally different, such as cancer, infection or even aging, have in common the alteration of the lipid composition in the membranes of the cells involved. One strategy proposed is the use of bacteria, cancer and senescent cell membranes as a therapeutic target so that their basic properties are perturbed, altering the membrane potential and inhibiting the control functions on the signaling, communication or production bioenergy processes.
Our research involves the application of computational techniques to explore the structure and function of biomolecules both alone and also interacting with lipid membranes. We have strong links with computational and experimental groups in biophysics, organic synthesis and medicine, both in academia and industry.
Although we are based in CiQUS, almost all of our computational experiments are carried out at Centro de Supercomputación de Galicia (CESGA)
Computational techniques:
Molecular Dynamics and Machine Learning to…
We are currently developing a database of multiscale molecular dynamics simulations of a number of natural AMPs and different lipid composition, modeling bacteria, tumor and senescent cells. This database (Supepmem, www.supepmem.com) will be used to extract dynamic descriptors containing mechanistic information to be analyzed by Machine Learning algorithms. The main objective of this project is to develop the first generation of antitumoral / antimicrobial agents designed from ‘hyper-predictive’ methods based on Molecular Dynamics simulations.
An alternative to lytic peptides involves the use of “intelligent” materials that form the active species only under some specific conditions, such as upon contact with tumor cell membrane, pH change or cancer receptor mediated answer. These synthetic antitumoral / antimicrobial peptidomimetics can be built from simpler components with low toxicity, acting by a process of molecular self-assembly at the cell membrane of the tumor cell. During the last years, and using both in-silico (multiscale simulations) and in-vitro methods, we have been studying the structure and dynamics of different cyclic peptides that self-assemble into peptide nanotubes in different environments, including the presence of a lipid membrane.
In collaboration with Underdog Pharmaceuticals, a spin-off of SENS Research Foundation, we are studying the mechanism followed by cyclodextrins to capture and to remove oxidized cholesterol derivatives, such as 7-ketocholesterol, from the membranes of senescent cells. These derivatives are broadly toxic molecules that our macrophages cannot digest, leading to the formation of bloated foam cells and deadly atherosclerosis. Using Molecular Dynamics Simulations we will try to shed light into the mechanism of interaction between engineered cyclodextrins and membranes of different composition.
RESEARCH IN COVID-19
We have recently published a study [Garcia-Fandino R, “Delving Into the Origin of Destructive Inflammation in COVID-19: A Betrayal of Natural Host Defense Peptides?“, Frontiers 2021, https://www.frontiersin.org/articles/10.3389/fimmu.2020.610024/full] where we show the correlation between the severity of the SARS-CoV-2 infection with the dramatic lipid alteration that the virus causes in the membranes of host cells, as well as the possible connection between what has been called persistent COVID and the sustained alteration of the lipid profile even in patients with undetectable viral load. In this same work, we propose that the mechanism that could explain these correlations is the response of the innate immune system, our first defense barrier, through antimicrobial peptides (AMPs), which precisely recognize and act by breaking membranes whose lipid composition is considered pathogenic. This scenario provides therapeutic intervention points focused to reestablish lipid composition or the blockage of specific AMPs involved in host self-destruction missions.
Reference: Garcia-Fandino R, “Delving Into the Origin of Destructive Inflammation in COVID-19: A Betrayal of Natural Host Defense Peptides?“, Frontiers 2021, https://www.frontiersin.org/articles/10.3389/fimmu.2020.610024/full
Making a comparison between CDs and the unique Ring of the legendary novel of The Lord of the Rings, J. R. R. Tolkien, the presence of these molecules in different treatments of COVID-19 have been reviewed. Their applications as encapsulating agents for antiviral drugs, as adjuvants to stabilize proteins or other molecules involved in the infection, adjuvants in vaccines, as cholesterol trappers to destabilize the virus capsid, as carriers for RNA therapies, as antivirals themselves, and even useful in anticoagulant therapies, highlight the great power of these sweet molecules. More than ever, we are in the situation to sub-scribe the words a thousand times pronounced by the dual character Gollum-Sméagol: “My precious”
https://www.sciencedirect.com/science/article/abs/pii/S0378517320306736
In order to understand and develop effective treatments against SARS-CoV-2, responsible for global pandemic we are currently living, a deep knowledge of the molecular structures involved in the infection process is key. Virtual reality (VR) is a powerful tool for studying biomolecular structures, enabling their visualization in stereoscopic 3D. We have recently published a reviewed the software implementations currently available for VR visualization of SARS-CoV-2 molecular structures, covering a range of virtual environments: CAVEs, desktop software, and cell phone applications, all of them combined with head-mounted devices like cardboards, Oculus Rift or the HTC Vive. We aim to impulse and facilitate the use of these emerging technologies in research against COVID-19 trying to increase the knowledge and thus minimizing risks before placing huge amounts of money for the development of potential treatments.
https://www.sciencedirect.com/science/article/pii/S2001037020304025
Taking advantage of our experience in the developing of augmented reality and virtual reality tools, we wanted to contribute to help to understand the 3D structure of some proteins involved in COVID-19. We developed CoronaVRus Coaster, a free application to navigate throughout SARS-CoV-2 proteins in VR, as if they were a roller coaster.
VISUALIZATION TECHNIQUES: WHEN SCIENCE MEETS ARTS.
The relationship between art and science has existed for a long time and now, with the digital revolution, it is speeding up. New forms of expression are appearing almost every day, leveraging the combined power of the rigorous scientific approach with the subjectivity and experimentalism of creative arts. These advances have allowed to introduce Science easier to more people, facilitating also the teaching process.
In our group, we have also tried to contribute to demolishing the wall between science and art, creating tools for real dissemination of scientific results using state-of-the-art visualization technologies, such as augmented reality (AR) and virtual reality (VR). Some examples are Ollomol for Captisol AR, Ollomol for Captisol VR, DimerDice, CoronaVRus coaster, NanotubAR, etc… all of them freely available for iOS and/or Android devices. All these tools have been developed in collaboration of our spin-off, MD.USE Innovations (www.mduse.com), created in 2015 from the results of our research group.
Our Applications
Captisol is a beta-cyclodextrin with an average of 7 sulfobutyl ether (SBE) substitutions per molecule that was designed to improve the solubility, stability, bioavailability, and dosage of biologically active compounds.
Ollomol AR for Captisol is an Augmented Reality (AR) molecular viewer developed to view 3D-AR films of certain Captisol-based supramolecular complexes. It allows to observe in an immersive way and with atomic resolution, the movement of its molecular structures, explicitly considering all the degrees of freedom. The films were generated from Molecular Dynamics simulations using GROMACS software and the GROMOS force field with a specific parameterization for Captisol (considering a structure with four SBE groups positioned in the C6-OH of glucose rings and three SBE groups placed on the C3 -OH of the remaining glucose rings of the cyclodextrin).
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Ollomol VR for Captisol is a Virtual Reality (VR) molecular viewer developed to visualize 3D-VR movies of complexes formed by Captisol with the following 12 drugs: allopregnanolone, amiodarone, carbamazepine, aripiprazole, busulfan, delafloxacin, carfilzomib, melphalan, posaconazole, maropitant, voriconazole and ziprasidone mesylate. The movies were generated by Molecular Dynamics simulations in explicit solvent using GROMACS. Water molecules were removed for clarity.
CellulAR is an educational application where you can see in three dimensions the different organelles of a eukaryotic and prokaryotic cell, using Augmented Reality.
The application is distributed with two trackers, each one corresponding to the eukaryotic and prokaryotic cell, respectively. By pointing the device at each of the trackers, a three-dimensional image of a cell section is projected where the most significant organelles of the cell are distinguished. Clicking on each of the organelles displays useful information about them.
This application has been developed by MD.USE Innovative Solutions SL (www.mduse.com) in collaboration with the Camilo José Cela University (UCJC).
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DimerDice allows visualizing different supramolecular dimeric complexes of cyclic peptides in Augmented Reality (AR). The cyclic peptides (CPs) are composed by γ-amino acids (cis-α,γ-aminocycloalkanecarboxylic acids, γ-Acas) alternated with α-amino acids (α,γ-CPs). These peptides containing γ-Acas can be designed from the original D,L-α-CPs just by replacing any α-amino acid for a γ-Aca of equivalent chirality. For instance, L-amino acids can be replaced by (1R,3S)-isomers while the (1S,3R)-Acas would substitute the D-enantiomers.
As part of an in-vitro/in-silico study carried out at Santiago de Compostela University to deeply analyze the preferred rearrangement adopted by α,γ-CPs, we explored all the possible combinations that could take place starting from two different monomers and their corresponding enantiomers.[1] This approach uses the selective N-methylation of the amide groups whose protons are not involved in hydrogen bonding interactions. The N-methylated residues are indicated in the figures of the trackers. Depending on the combination of monomers, a parallel or an antiparallel arrangement is possible.
Pointing with the device to each tracker separately, an AR image of the corresponding monomer is viewed. When the tracker images of two monomers are placed close to each other, the structure of the dimer formed by that combination of cyclic peptides is shown.
Full geometry optimizations of the dimers and monomers were carried out with the B3LYP functional and the standard 6-31G(d) basis set. All of the DFT calculations reported in this study were performed with the Gaussian 16 package.
This application was specifically developed by Santiago de Compostela University (Spain) and MD.USE Innovative Solutions S.L. (www.mduse.com).
[1] Manuscript in preparation.
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“Nanoscience” is the branch of science that is responsible for the study of objects at the nanometric scale, that is, those whose sizes are between 1 and 100 nm. One of the great challenges of nanotechnology is the preparation of new functional materials whose dimensions and structures are controlled at the molecular or atomic level. In chemistry, nanotubes are called tubular (cylindrical) structures, whose diameter is the size of a nanometer.
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Download Bits of SugAR, introduce the code corresponding to a CD from any collection and experience the magic of augmented reality to see the beauty of these molecules.