Feira de Ciência – New Software Applications for Biomolecular Simulations

New Software Applications for Biomolecular Simulations: Applications to Chemistry and Biochemistry.

CHEMTECH DQB – Chemistry Technology Events at DQB – 2018

March 8th, 2018 – Departamento de Química e Bioquímica da Faculdade de Ciências da Universidade do Porto

Descrição da Atividade

Realizou-se no Departamento de Química e Bioquímica da Faculdade de Ciências da Universidade do Porto uma mini feira de ciência onde se mostraram os softwares desenvolvidos no grupo de Bioquímica Teórica e Computacional. Os softwares são todos eles extensões para o VMD (Visual Molecular Dynamics) um visualizador molecular gratuito desenvolvido pela Universidade Illinois.

Os participantes tiveram a oportunidade de falar com os desenvolvedores e experimentar os softwares, que sendo gratuitos podem ser mais tarde instalados e usados por cada um dos participantes.

Fica aqui o folheto que foi distribuído na sessão demonstrativa: Download

E ainda algumas fotografias do evento:

Organização

André F. Pina
Carla S. S. Teixeira
Henrique S. Fernandes
Juliana F. Rocha
Nuno M. F. S. A. Cerqueira
Sérgio F. Sousa

molUP: a VMD plugin to handle QM and ONIOM calculations using the Gaussian software

Henrique Silva Fernandes, Maria João Ramos, and Nuno M.F.S.A. Cerqueira

Published on 21st February 2018
DOI: http://dx.doi.org/10.1002/jcc.25189 | Download citation

Abstract

The notable advances obtained by computational (bio)chemistry provided its widespread use in many areas of science, in particular, in the study of reaction mechanisms. These studies involve a huge number of complex calculations, which are often carried out using the Gaussian suite of programs. The preparation of input files and the analysis of the output files are not easy tasks and often involve laborious and complex steps. Taking this into account, we developed molUP: a VMD plugin that offers a complete set of tools that enhance the preparation of QM and ONIOM (QM/MM, QM/QM, and QM/QM/MM) calculations. The starting structures for these calculations can be imported from different chemical formats. A set of tools is available to help the user to examine or modify any geometry parameter. This includes the definition of layers in ONIOM calculations, choosing fixed atoms during geometry optimizations, the recalculation or adjustment of the atomic charges, performing SCANs or IRC calculations, etc. molUP also extracts the geometries from the output files as well as the energies of each of them. All of these tasks are performed in an interactive GUI that is extremely helpful for the user. MolUP was developed to be easy to handle by inexperienced users, but simultaneously to be a fast and flexible graphical interface to allow the advanced users to take full advantage of this plugin. The program is available, free of charges, for macOS, Linux, and Windows at the PortoBioComp page https://www.fc.up.pt/PortoBioComp/database/doku.php?id=molup.

Volta ao Conhecimento – 79ª Volta a Portugal em Bicicleta

No dia 13 de agosto de 2017, o grupo de Bioquímica Teórica e Computacional esteve representado na Feira da 79ª Volta a Portugal em Bicicleta, no âmbito do projeto Volta ao Conhecimento promovido pelo Ministério da Ciência, Tecnologia e Ensino Superior.

O stand esteve montado junto à meta da 8ª etapa em Oliveira de Azeméis e contou com a participação de vários cidadãos que se deslocaram para assistir ao término de mais uma etapa da Volta.

Optámos por montar umm stand muito interativo com uma máquina de jogos educativa, o ProteinWars, cujo o objetivo é mostrar de que forma estudamos as proteínas e as moléculas para desenvolver novos fármacos.

Além disso, um segundo computador com um joystick acoplado permitiu aos participantes visualizarem moléculas e interagirem com os átomos em simulações moleculares.

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The Catalytic Mechanism of the Pyridoxal-5′-phosphate-Dependent Enzyme, Histidine Decarboxylase: A Computational Study

Henrique Silva Fernandes, Maria João Ramos, and Nuno M.F.S.A. Cerqueira

Published on June 14th 2017
DOI: http://dx.doi.org/10.1002/chem.201701375 | Download citation

Abstract

The catalytic mechanism of histidine decarboxylase (HDC), a pyridoxal-5′-phosphate (PLP)-dependent enzyme, was studied by using a computational QM/MM approach following the scheme M06-2X/6–311++G(3df,2pd):Amber. The reaction involves two sequential steps: the decarboxylation of l-histidine and the protonation of the generated intermediate from which results histamine. The rate-limiting step is the first one (ΔG=17.6 kcal mol−1; ΔGr=13.7 kcal mol−1) and agrees closely with the available experimental kcat (1.73 s−1), which corresponds to an activation barrier of 17.9 kcal mol−1. In contrast, the second step is very fast (ΔG=1.9 kcal mol−1) and exergonic (ΔGr=−33.2 kcal mol−1). Our results agree with the available experimental data and allow us to explain the role played by several active site residues that are considered relevant according to site-directed mutagenesis studies, namely Tyr334B, Asp273A, Lys305A, and Ser354B. These results can provide insights regarding the catalytic mechanism of other enzymes belonging to family II of PLP-dependent decarboxylases.

Nanostructures for Cancer Therapy – Elsevier

Editors: Alexandru Grumezescu Anton Ficai
eBook ISBN: 9780323461504
Hardcover ISBN: 9780323461443
Imprint: Elsevier
Published Date: 14th April 2017
Page Count: 920

Nanostructures for Cancer Therapy discusses the available preclinical and clinical nanoparticle technology platforms and their impact on cancer therapy, including current trends and developments in the use of nanostructured materials in chemotherapy and chemotherapeutics.

In particular, coverage is given to the applications of gold nanoparticles and quantum dots in cancer therapies. In addition to the multifunctional nanomaterials involved in the treatment of cancer, other topics covered include nanocomposites that can target tumoral cells and the release of antitumoral therapeutic agents.

The book is an up-to-date overview that covers the inorganic and organic nanostructures involved in the diagnostics and treatment of cancer.

Chapter 24 – Cancer Therapies Based on Enzymatic Amino Acid Depletion

Carla Teixeira*, Henrique Fernandes*, P. A. Fernandes, M. J. Ramos and Nuno M. F. S. A. Cerqueira (* contributed equally to this work)

Buy on Elsevier | Buy on Amazon | Available on iTunes | Preview

Image 1.jpg

 

Abstract

A growing understanding of tumor biology has allowed the identification of various cellular characteristics that are more frequently associated with cancer cells than with normal cells. These findings have prompted the development of new therapeutics specifically designed to exploit these differences. In this context, the amino acid depriving enzymes have shown very promising results and proven to be active and very specific against various types of cancers. These therapies involve the depletion of specific amino acids in the bloodstream that cannot be synthesized by tumor cells. This happens because these cells often have a defecting enzymatic armamentarium and therefore rely on external supply for those amino acids. Decreasing the concentration of certain amino acids in blood has thus been shown to impair the development or even destroy tumor cells. Normal cells remain unaltered since they are less demanding and/or can synthesize these compounds in sufficient amounts by other mechanisms.

In this chapter, the structure, function, catalytic mechanism and therapeutic application of some amino acid depriving enzymes will be reviewed. Particular attention will be given to enzymes that have potential or are currently used in the treatment of several types of cancer, namely: (1) l-asparaginase used for the treatment of acute lymphoblastic leukemia; (2) l-arginase and l-arginine deiminase that are used in the therapy of hepatocellular carcinomas and melanomas, two diseases that account annually with approximately 1 million of new cases and for which there is currently no efficacious treatment; and (3) l-Methioninase with potential to be used in the treatment of breast, colon, lung, and renal cancers.

Keywords

  • amino acid deprivation;
  • heterologous enzymes;
  • tumor;
  • cancer;
  • catalytic mechanism;
  • asparaginase;
  • methioninase;
  • arginase;
  • arginine deaminase

Poster | 5º Encontro Português de Jovens Químicos (PYCheM) and 1st European Young Chemists Meeting

Centro Cultural Vila Flor, Guimarães

2016, 22th to 24th April

Poster: “Computational studies addressed to the catalytic mechanism of Histidine Decarboxylase”

Henrique S. Fernandes (1), Maria João Ramos, Nuno M. F. S. A. Cerqueira (1)

(1) UCIBIO/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, PT

Mammalian histidine decarboxylase (mHDC) is an enzyme that requires pyridoxal-5′-phosphate (PLP) as a cofactor [1-3]. mHDC belongs to the group II of PLP-dependent decarboxylases together with L-DOPA and glutamate decarboxylases, and catalyses the L-histidine decarboxylation from which results histamine.

Histamine plays a key role in several biological events such as immune response, gastric system modulation and as a neurotransmitter in the nervous system. Several inhibitors for histamine action have been studied in order to treat some diseases such as atopic dermatitis, allergies, and cancer.

mHDC has been studied for a long time, but only in 2012 Komori’s [2] group was able to determine the X-ray structure of the enzyme and revealed the active site environment. Till date, only hypothesis about the catalytic mechanism of mHDC were available and based on homology models (that propose a different active site configuration).

In this work, we studied the catalytic mechanism of mHDC by computational approaches using the recent X-ray structure of mHDC (PDB code: 4E1O [4]) and a QM/MM methodology.

The results have shown that mHDC catalyses the reaction in a two-step type of mechanism. The first step involves a decarboxylation that is followed by the formation of a stable carbanion. In the second step, the carbanion is protonated by a base from which results histamine.

[1] Ngo, H. P., Cerqueira, N. M., Kim, J. K., Hong, M. K., Fernandes, P. A., Ramos, M. J., and Kang, L. W., Acta crystallographica. Section D, Biological crystallography 2014, 70, 596-606

[2] Oliveira, Eduardo F.; Cerqueira, Nuno M. F. S. A.; Fernandes, Pedro A. and Ramos, M.J., Journal of the American Chemical Society 2011, 133, 15496-15505

[3] Cerqueira, N. M. F. S. A.; Fernandes, P. A.; Ramos, M. J., Journal of Chemical Theory and Computation 2011, 7, 1356-1368

[4] Komori, H., Nitta, Y., Ueno, H., and Higuchi, Y., Acta Crystallogr Sect F Struct Biol Cryst Commun 2012, 68, 675-677

 

Poster | Encontro de Jovens Investigadores em Biologia Computacional Estrutural

Instituto Pedro Nunes, Coimbra

2015, 18th December

Poster: “Computational studies addressed to the catalytic mechanism of Histidine Decarboxylase”

Henrique S. Fernandes (1), Nuno M. F. S. A. Cerqueira (1)

(1) UCIBIO/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, PT

Mammalian histidine decarboxylase (mHDC) is an enzyme that requires pyridoxal-5′-phosphate (PLP) as a cofactor [1]. mHDC belongs to the group II of PLP-dependent decarboxylases together with L-DOPA and glutamate decarboxylases, and catalyses the L-histidine decarboxylation from which results histamine.

Histamine plays a key role in several biological events such as immune response, gastric system modulation and as a neurotransmitter in the nervous system. Several inhibitors for histamine action have been studied in order to treat some diseases such as atopic dermatitis, allergies, and cancer.

mHDC has been studied for a long time, but only in 2012 Komori’s [2] group was able to determine X-ray structure of the enzyme and revealed the active site environment. Until date, only hypothesis about the mechanism of mHDC were available and based on homology models (that propose a different active site configuration).

In this work we are studying the catalytic mechanism of mHDC by computational means using the recent X-ray structure of mHDC and a QM/MM methodology.

The results have shown that mHDC catalyses the reaction in a two-step type of mechanism. The first step involves a decarboxylation that is followed by the formation of a carbanion. In the second step, the carbanion is protonated by a base from which results histamine. Our early results indicate that the first step is the limiting reaction step and the full reaction is endothermic by approximately 25 kcal/mol.

[1] Ngo HP, Cerqueira NMFSA, Kim JK, Hong MK, Fernandes PA, et al. 2014. Acta Crystallogr D Biol Crystallogr 70: 596-606;
[2] Komori H, Nitta Y, Ueno H, Higuchi Y. 2012. Acta Crystallogr Sect F Struct Biol Cryst Commun 68: 675-7

Abstracts’ Book | Web Page

Amino Acid Deprivation Using Enzymes as a Targeted Therapy for Cancer and Viral Infections

Pages 283-297 | Received 29 Jul 2016, Accepted 25 Oct 2016, Accepted author version posted online: 04 Nov 2016, Published online: 15 Nov 2016

Introduction: Amino acid depletion in the blood serum is currently being exploited and explored for therapies in tumors or viral infections that are auxotrophic for a certain amino acid or have a metabolic defect and cannot produce it. The success of these treatments is because normal cells remain unaltered since they are less demanding and/or can synthesize these compounds in sufficient amounts for their needs by other mechanisms.

Areas covered: This review is focused on amino acid depriving enzymes and their formulations that have been successfully used in the treatment of several types of cancer and viral infections. Particular attention will be given to the enzymes L-asparaginase, L-arginase, L-arginine deiminase, and L-methionine-γ-lyase.

Expert opinion: The immunogenicity and other toxic effects are perhaps the major limitations of these therapies, but they have been successfully decreased either through the expression of these enzymes from other organisms, recombination processes, pegylation of the selected enzymes or by specific mutations in the proteins. In 2006, FDA has already approved the use of L-asparaginase in the treatment of acute lymphoblastic leukemia. Other enzymes and in particular L-arginase, L-arginine deiminase, and L-methioninase have been showing promising results in vitro and in vivo studies.

oniomFROZEN

oniomANALYSIS is a TCL script that allows an easy way to change the frozen status of each atom in Gaussian Hybrid Systems (ONIOM).

How to use?

Insert follow command in shell:

tclsh oniomFROZEN.tcl [A] [B] [C]

Where:

[A] is a flag which defines what type of job is going to be perfomed:

–readfile : residues of file \[C\] will be unfrozen and all others will be frozen

–frozenall : all atoms will be frozen

–unfrozenall : all atoms will be unfrozen

–invert : all previous unfrozen atoms will be frozen and all previous frozen atoms will be unfrozen

–invertnowater : equal to previous but all water molecules \(ResName=WAT\) will be frozen

[B] is the Gaussian 09 input file (.com)

[C] is a file with a list of residues (one number per line) to become unfrozen, frozen all other residues. ONLY works with the –readfile flag.

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DOI