Instytut Podstawowych Problemów Techniki
Polskiej Akademii Nauk


dr Luis Cofas Vargas

Zakład Biosystemów i Miękkiej Materii (ZBiMM)
Pracownia Modelowania w Biologii i Medycynie (PMBM)
stanowisko: adiunkt
telefon: (+48) 22 826 12 81 wewn.: 423
pokój: 328
ORCID: 0000-0001-5603-1437

2022-12-06 Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase  (Chemistry Institute, UNAM)
promotor -- dr Enrique García-Hernandez, Chemistry Institute, UNAM
kopromotor -- dr Diego Prada-Gracia, Computational Biology and Drug Design Research Unit. Hospital Infantil de México Federico Gómez
kopromotor -- dr Hector Riveros-Rosas, School of Medicine, UNAM

Ostatnie publikacje
1.  Cofas Vargas L.F., Azevedo Rodrigo M., Poblete S., Chwastyk M., Poma Bernaola A.M., The GōMartini Approach: Revisiting the Concept of Contact Maps and the Modelling of Protein Complexes, ACTA PHYSICA POLONICA A, ISSN: 0587-4246, DOI: 10.12693/APhysPolA.145.S9, Vol.145, No.3, pp.S9-S20, 2024

We present a review of a series of contact maps for the determination of native interactions in proteins and nucleic acids based on a distance threshold. Such contact maps are mostly based on physical and chemical construction, and yet they are sensitive to some parameters (e.g., distances or atomic radii) and can neglect some key interactions. Furthermore, we also comment on a new class of contact maps that only requires geometric arguments. The contact map is a necessary ingredient to build a robust Gō-Martini model for proteins and their complexes in the Martini 3 force field. We present the extension of a popular structure-based Gō--like approach to the study of protein–sugar complexes, and the limitations of this approach are also discussed. The Gō-Martini approach was first introduced by Poma et al. (J. Chem. Theory Comput. 13, 1366 (2017)) in Martini 2 force field, and recently, it has gained the status of gold standard for protein simulation undergoing conformational changes in Martini 3 force field. We discuss several studies that have provided support for this approach in the context of the biophysical community.

Słowa kluczowe:
Martini 3,Structure-based coarse-graining,SMFS,biomolecules,GoMartini

Afiliacje autorów:
Cofas Vargas L.F. - inna afiliacja
Azevedo Rodrigo M. - inna afiliacja
Poblete S. - inna afiliacja
Chwastyk M. - Institute of Physics, Polish Academy of Sciences (PL)
Poma Bernaola A.M. - inna afiliacja
2.  Titaux-Delgado G., Lopez-Giraldo Andrea E., Carrillo E., Cofas-Vargas Luis F., Carranza Luis E., Lopez-Vera E., García-Hernandez E., del Rio-Portilla F., Beta-KTx14.3, a scorpion toxin, blocks the human potassium channel KCNQ1, Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, ISSN: 1570-9639, DOI: 10.1016/j.bbapap.2023.140906, Vol.1871, No.4, pp.140906-1-11, 2023

Potassium channels play a key role in regulating many physiological processes, thus, alterations in their proper functioning can lead to the development of several diseases. Hence, the search for compounds capable of regulating the activity of these channels constitutes an intense field of investigation. Potassium scorpion toxins are grouped into six subfamilies (α, β, γ, κ, δ, and λ). However, experimental structures and functional analyses of the long chain β-KTx subfamily are lacking. In this study, we recombinantly produced the toxins TcoKIK and beta-KTx14.3 present in the venom of Tityus costatus and Lychas mucronatus scorpions, respectively. The 3D structures of these β-KTx toxins were determined by nuclear magnetic resonance. In both toxins, the N-terminal region is unstructured, while the C-terminal possesses the classic CSα/β motif. TcoKIK did not show any clear activity against frog Shaker and human KCNQ1 potassium channels; however, beta-KTx14.3 was able to block the KCNQ1 channel. The toxin-channel interaction mode was investigated using molecular dynamics simulations. The results showed that this toxin could form a stable network of polar-to-polar and hydrophobic interactions with KCNQ1, involving key conserved residues in both molecular partners. The discovery and characterization of a toxin capable of inhibiting KCNQ1 pave the way for the future development of novel drugs for the treatment of human diseases caused by the malfunction of this potassium channel.
Statement of significance

Scorpion toxins have been shown to rarely block human KCNQ1 channels, which participate in the regulation of cardiac processes. In this study, we obtained recombinant beta-KTx14.3 and TcoKIK toxins and determined their 3D structures by nuclear magnetic resonance. Electrophysiological studies and molecular dynamics models were employed to examine the interactions between these two toxins and the human KCNQ1, which is the major driver channel of cardiac repolarization; beta-KTx14.3 was found to block effectively this channel. Our findings provide insights for the development of novel toxin-based drugs for the treatment of cardiac channelopathies involving KCNQ1-like channels.

Słowa kluczowe:
β-KTx, Scorpion toxins, Cysteine-stabilized α/β motif, TcoKIK, Beta-KTx14.3, KCNQ1

Afiliacje autorów:
Titaux-Delgado G. - inna afiliacja
Lopez-Giraldo Andrea E. - inna afiliacja
Carrillo E. - inna afiliacja
Cofas-Vargas Luis F. - IPPT PAN
Carranza Luis E. - inna afiliacja
Lopez-Vera E. - inna afiliacja
García-Hernandez E. - inna afiliacja
del Rio-Portilla F. - inna afiliacja
3.  Cofas-Vargas Luis F., Mendoza-Espinosa P., Avila-Barrientos Luis P., Prada-Gracia D., Riveros-Rosas H., García-Hernández E., Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase, Frontiers in Pharmacology, ISSN: 1663-9812, DOI: 10.3389/fphar.2022.1012008, Vol.13, pp.1012008-1-19, 2022

In addition to playing a central role in the mitochondria as the main producer of ATP, FOF1-ATP synthase performs diverse key regulatory functions in the cell membrane. Its malfunction has been linked to a growing number of human diseases, including hypertension, atherosclerosis, cancer, and some neurodegenerative, autoimmune, and aging diseases. Furthermore, inhibition of this enzyme jeopardizes the survival of several bacterial pathogens of public health concern. Therefore, FOF1-ATP synthase has emerged as a novel drug target both to treat human diseases and to combat antibiotic resistance. In this work, we carried out a computational characterization of the binding sites of the fungal antibiotic aurovertin in the bovine F1 subcomplex, which shares a large identity with the human enzyme. Molecular dynamics simulations showed that although the binding sites can be described as preformed, the inhibitor hinders inter-subunit communications and exerts long-range effects on the dynamics of the catalytic site residues. End-point binding free energy calculations revealed hot spot residues for aurovertin recognition. These residues were also relevant to stabilize solvent sites determined from mixed-solvent molecular dynamics, which mimic the interaction between aurovertin and the enzyme, and could be used as pharmacophore constraints in virtual screening campaigns. To explore the possibility of finding species-specific inhibitors targeting the aurovertin binding site, we performed free energy calculations for two bacterial enzymes with experimentally solved 3D structures. Finally, an analysis of bacterial sequences was carried out to determine conservation of the aurovertin binding site. Taken together, our results constitute a first step in paving the way for structure-based development of new allosteric drugs targeting FOF1-ATP synthase sites of exogenous inhibitors.

Słowa kluczowe:
FOF1-ATP synthase inhibition, conformational dynamics, solvent sites, binding free energy, hot spot binding residues, bacterial pathogens

Afiliacje autorów:
Cofas-Vargas Luis F. - IPPT PAN
Mendoza-Espinosa P. - inna afiliacja
Avila-Barrientos Luis P. - inna afiliacja
Prada-Gracia D. - inna afiliacja
Riveros-Rosas H. - inna afiliacja
García-Hernández E. - inna afiliacja
4.  Avila-Barrientos Luis P., Cofas-Vargas Luis F., Agüero-Chapin G., García-Hernandez E., Ruiz-Carmona S., Valdez-Cruz Norma A., Trujillo-Roldán M., Weber J., Ruiz-Blanco Yasser B., Barril X., García-Hernández E., Computational Design of Inhibitors Targeting the Catalytic β Subunit of Escherichia coli FOF1-ATP Synthase, Antibiotics, ISSN: 2079-6382, DOI: 10.3390/antibiotics11050557, Vol.11, No.5, pp.557-1-19, 2022

With the uncontrolled growth of multidrug-resistant bacteria, there is an urgent need to search for new therapeutic targets, to develop drugs with novel modes of bactericidal action. FoF1-ATP synthase plays a crucial role in bacterial bioenergetic processes, and it has emerged as an attractive antimicrobial target, validated by the pharmaceutical approval of an inhibitor to treat multidrug-resistant tuberculosis. In this work, we aimed to design, through two types of in silico strategies, new allosteric inhibitors of the ATP synthase, by targeting the catalytic β subunit, a centerpiece in communication between rotor subunits and catalytic sites, to drive the rotary mechanism. As a model system, we used the F1 sector of Escherichia coli, a bacterium included in the priority list of multidrug-resistant pathogens. Drug-like molecules and an IF1-derived peptide, designed through molecular dynamics simulations and sequence mining approaches, respectively, exhibited in vitro micromolar inhibitor potency against F1. An analysis of bacterial and Mammalia sequences of the key structural helix-turn-turn motif of the C-terminal domain of the β subunit revealed highly and moderately conserved positions that could be exploited for the development of new species-specific allosteric inhibitors. To our knowledge, these inhibitors are the first binders computationally designed against the catalytic subunit of FOF1-ATP synthase.

Słowa kluczowe:
FOF1-ATP synthase, allosteric inhibition, structure-based drug design, evolutionary and PPI algorithms, peptide design

Afiliacje autorów:
Avila-Barrientos Luis P. - inna afiliacja
Cofas-Vargas Luis F. - IPPT PAN
Agüero-Chapin G. - inna afiliacja
García-Hernandez E. - inna afiliacja
Ruiz-Carmona S. - inna afiliacja
Valdez-Cruz Norma A. - inna afiliacja
Trujillo-Roldán M. - inna afiliacja
Weber J. - inna afiliacja
Ruiz-Blanco Yasser B. - inna afiliacja
Barril X. - inna afiliacja
García-Hernández E. - inna afiliacja
5.  Labra-Núñez A., Cofas-Vargas Luis F., Gutiérrez-Magdaleno G., Gómez-Velasco H., Rodríguez-Hernández A., Rodríguez-Romero A., García-Hernández E., Energetic and structural effects of the Tanford transition on ligand recognition of bovine β-lactoglobulin, Archives of Biochemistry and Biophysics, ISSN: 0003-9861, DOI: 10.1016/, Vol.699, pp.108750-1-11, 2021

Bovine β-lactoglobulin, an abundant protein in whey, is a promising nanocarrier for peroral administration of drug-like hydrophobic molecules, a process that involves transit through the different acidic conditions of the human digestive tract. Among the several pH-induced conformational rearrangements that this lipocalin undergoes, the Tanford transition is particularly relevant. This transition, which occurs with a midpoint around neutral pH, involves a conformational change of the E-F loop that regulates accessibility to the primary binding site. The effect of this transition on the ligand binding properties of this protein has scarcely been explored. In this study, we carried out an energetic and structural characterization of β-lactoglobulin molecular recognition at pH values above and below the zone in which the Tanford transition occurs. The combined analysis of crystallographic, calorimetric, and molecular dynamics data sheds new light on the interplay between self-association, ligand binding, and the Tanford pre- and post-transition conformational states, revealing novel aspects underlying the molecular recognition mechanism of this enigmatic lipocalin.

Słowa kluczowe:
Lipocalin, Structural energetics, Isothermal titration calorimetry, Molecular dynamics, X-ray crystallography

Afiliacje autorów:
Labra-Núñez A. - inna afiliacja
Cofas-Vargas Luis F. - IPPT PAN
Gutiérrez-Magdaleno G. - inna afiliacja
Gómez-Velasco H. - inna afiliacja
Rodríguez-Hernández A. - inna afiliacja
Rodríguez-Romero A. - inna afiliacja
García-Hernández E. - inna afiliacja
6.  Valdez Cruz Norma A., García Hernández E., Espitia C., Cobos Marín L., Altamirano C., Bando Campos Carlos G., Cofas-Vargas Luis F., Coronado Aceves Enrique W., González Hernández Ricardo A., Hernández Peralta P., Juárez López D., Ortega Portilla Paola A., Restrepo Pineda S., Zelada Cordero P., Trujillo Roldán Mauricio A., Integrative overview of antibodies against SARS-CoV-2 and their possible applications in COVID-19 prophylaxis and treatment, Microbial Cell Factories, ISSN: 1475-2859, DOI: 10.1186/S12934-021-01576-5, Vol.20, pp.88-1-32, 2021

SARS-CoV-2 is a novel β-coronavirus that caused the COVID-19 pandemic disease, which spread rapidly, infecting more than 134 million people, and killing almost 2.9 million thus far. Based on the urgent need for therapeutic and prophylactic strategies, the identification and characterization of antibodies has been accelerated, since they have been fundamental in treating other viral diseases. Here, we summarized in an integrative manner the present understanding of the immune response and physiopathology caused by SARS-CoV-2, including the activation of the humoral immune response in SARS-CoV-2 infection and therefore, the synthesis of antibodies. Furthermore, we also discussed about the antibodies that can be generated in COVID-19 convalescent sera and their associated clinical studies, including a detailed characterization of a variety of human antibodies and identification of antibodies from other sources, which have powerful neutralizing capacities. Accordingly, the development of effective treatments to mitigate COVID-19 is expected. Finally, we reviewed the challenges faced in producing potential therapeutic antibodies and nanobodies by cell factories at an industrial level while ensuring their quality, efficacy, and safety.

Afiliacje autorów:
Valdez Cruz Norma A. - inna afiliacja
García Hernández E. - inna afiliacja
Espitia C. - inna afiliacja
Cobos Marín L. - inna afiliacja
Altamirano C. - inna afiliacja
Bando Campos Carlos G. - inna afiliacja
Cofas-Vargas Luis F. - IPPT PAN
Coronado Aceves Enrique W. - inna afiliacja
González Hernández Ricardo A. - inna afiliacja
Hernández Peralta P. - inna afiliacja
Juárez López D. - inna afiliacja
Ortega Portilla Paola A. - inna afiliacja
Restrepo Pineda S. - inna afiliacja
Zelada Cordero P. - inna afiliacja
Trujillo Roldán Mauricio A. - inna afiliacja

Abstrakty konferencyjne
1.  Cofas Vargas Luis., Poma Bernaola A., Capturing the biomechanics of SARS-COV-2/antibody complexes by GōMartini simulation, BPS 2024, Biophysical Society 68th Annual Meeting, 2024-02-10/02-14, Pennsylvania (US), pp.44a, 2024

Molecular dynamics (MD) simulation is a powerful tool for revealing the underlying mechanisms governing protein mechanostability. A typical disadvantage of the all-atom representation is the use of pulling speeds several orders of magnitude higher than those employed in single- molecule force spectroscopy (SMFS). In contrast, coarse-grained (CG) representation has the advantage of reducing the computational cost at the cost of losing information on the interaction strength at protein interfaces. This effect is more pronounced in protein complexes. The GōMartini approach is analternative tool to circumvent this limitation, and in its recent implementation, it employs virtual sites near the C-alpha atom positions in the Martini 3 force field. This approach requires the determination of a contact map that includes the most relevant interactions between residues (i.e., native contacts). Large-scale applications, including mechanical stability and conformational changes, can be studied using the GōMartini. In this work, we have applied this approach to study the mechanostability associated with the immune response. Through refinement of the interaction potential between residues at the interface of the protein complex, we reproduced the results of all-atom MD and contrasted them with reported experimental values. GōMartini approach allows us to approach the speeds of atomic force microscopy (AFM) cantilevers in SMFS while preserving crucial information about the interaction between residues. This method is extremely useful in identifying the most crucial interactions that are responsible for the enhanced mechanostability in SARS-CoV-2 variants, information that can be used to develop antibodies with greater affinity.

Słowa kluczowe:
SARS-CoV-2, immune evasion, coarse-graining, GōMartini, MD simulation, mAb, nanomechanics

Afiliacje autorów:
Cofas Vargas Luis. - IPPT PAN
Poma Bernaola A. - IPPT PAN
2.  Cofas Vargas L.F., Mendoza-Espinosa P., Garcia-Hernandez E., Molecular Basis for FOF1-ATP Synthase Allosteric Drug Development: Aurovertin Binding Site, Hybrid Workshop on Computer Simulation and Theory of Macromolecules, 2023-04-28/04-29, Hybrid (Hünfeld and virtual) (DE), No.Poster 158, pp.1, 2023
3.  Cofas-Vargas L.F., Garcia-Hernandez E., ATP sintasa y el diseño potencial de inhibidores alostéricos especie-específicos, SIBNAA2021, Simposio Internacional de Busqueda de Nuevas Alternativas Antimicrobianas, 2021-03-11/03-13, virtual (CO), pp.53, 2021

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