Quantum mechanics/molecular mechanics studies of the mechanism of cysteine protease inhibition by peptidyl-2,3-epoxyketones

2017 ◽  
Vol 19 (20) ◽  
pp. 12740-12748 ◽  
Author(s):  
Kemel Arafet ◽  
Silvia Ferrer ◽  
Florenci V. González ◽  
Vicent Moliner
Keyword(s):  
Quantum Mechanics ◽  
Life Cycle ◽  
Molecular Mechanics ◽  
Cysteine Protease ◽  
Therapeutic Targets ◽  
Cysteine Proteases ◽  
Protease Inhibition ◽  
Parasitic Protozoa

Cysteine proteases are the most abundant proteases in parasitic protozoa and they are essential enzymes to sustain the life cycle of several of them, thus becoming attractive therapeutic targets for the development of new inhibitors.

scholarly journals Equilibrium Between Tri- and Tetra-Coordinate Chalcogenuranes Is Critical for Cysteine Protease Inhibition

2020 ◽  
Author(s):  
Gabriela Dias SIlva ◽  
Rodrigo L O R Cunha ◽  
Mauricio Domingues Coutinho Neto
Keyword(s):  
Cysteine Protease ◽  
Density Functional ◽  
Active Form ◽  
Sulfhydryl Group ◽  
Cysteine Proteases ◽  
Inhibition Mechanism ◽  
Direct Reaction ◽  
Exchange Reactions ◽  
Protease Inhibition ◽  
Biological Media

<div>There have been significant advances in the biological use of hypervalent selenium and tellurium compounds as cysteine protease inhibitors over the recent past. However, the full understanding of their reaction mechanisms in aqueous medium and the mechanism of cysteine proteases inhibition is still elusive. Kinetic studies suggest an irreversible inhibition mechanism, which was explained by forming a covalent bond between the enzyme sulfhydryl group and the chalcogen atom at its hypervalent state (+4). However, it is still unclear the active form of the inhibitor present in the aqueous biological media. To uncover this question, we performed a theoretical investigation using density functional theory (DFT). This study investigated chloride ligand exchange reactions by oxygen and sulfur nucleophiles on hypervalent selenium and tellurium compounds. All tetra- and tri-coordinate chalcogen compounds and distinct protonation states of the nucleophiles were considered, totaling 34 unique species, 7</div><div>nucleophiles and 155 free energies rections. We discovered that chloride is easily replaced by a nonprotonated nucleophile (SH<sup>–</sup> or OH<sup>– </sup>) in R<sub>2</sub>SeCl<sub>2</sub> . We also found that</div><div>tri-coordinate species are more stable than their tetra-coordinate counterparts, with selenoxide (R<sub>2</sub>SeO) protonation being strongly exergonic in acid pH. These results suggest that the protonated selenoxide (R<sub>2</sub>SeOH<sup>+</sup>) is the most probable active chemical species in biological media. The computed energetic profiles paint a possible picture for the selenurane activity, with successive exergonic steps leading to a covalent inhibition of thiol dependent enzymes, like cysteine proteases. A second less exergonic pathway has also been uncovered, with a direct reaction to chalcogenonium cation (R<sub>2</sub>SeCl<sup>+</sup>) as the inhibition step. The trends observed for the telluranes were similar, albeit with</div><div>more exergonic reactions and a stronger trend to form bonds with oxygen species then selenuranes.</div><div><br></div>

scholarly journals Using serpins cysteine protease cross-specificity to possibly trap SARS-CoV-2 Mpro with reactive center loop chimera

2020 ◽  
Vol 134 (17) ◽  
pp. 2235-2241
Author(s):  
Mohamad Aman Jairajpuri ◽  
Shoyab Ansari
Keyword(s):  
Cysteine Protease ◽  
Active Site ◽  
Cleavage Site ◽  
Serine Proteases ◽  
Therapeutic Potential ◽  
Cysteine Proteases ◽  
Protease Inhibition ◽  
Reactive Center Loop ◽  
Main Protease ◽  
Reactive Center

Abstract Human serine protease inhibitors (serpins) are the main inhibitors of serine proteases, but some of them also have the capability to effectively inhibit cysteine proteases. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) main protease (Mpro) is a chymotrypsin-type cysteine protease that is needed to produce functional proteins essential for virus replication and transcription. Serpin traps its target proteases by presenting a reactive center loop (RCL) as protease-specific cleavage site, resulting in protease inactivation. Mpro target sites with its active site serine and other flanking residues can possibly interact with serpins. Alternatively, RCL cleavage site of serpins with known evidence of inhibition of cysteine proteases can be replaced by Mpro target site to make chimeric proteins. Purified chimeric serpin can possibly inhibit Mpro that can be assessed indirectly by observing the decrease in ability of Mpro to cleave its chromogenic substrate. Chimeric serpins with best interaction and active site binding and with ability to form 1:1 serpin–Mpro complex in human plasma can be assessed by using SDS/PAGE and Western blot analysis with serpin antibody. Trapping SARS-CoV-2 Mpro cysteine protease using cross-class serpin cysteine protease inhibition activity is a novel idea with significant therapeutic potential.

scholarly journals Equilibrium Between Tri- and Tetra-Coordinate Chalcogenuranes Is Critical for Cysteine Protease Inhibition

2020 ◽  
Author(s):  
Gabriela Dias SIlva ◽  
Rodrigo L O R Cunha ◽  
Mauricio Domingues Coutinho Neto
Keyword(s):  
Cysteine Protease ◽  
Density Functional ◽  
Active Form ◽  
Sulfhydryl Group ◽  
Cysteine Proteases ◽  
Inhibition Mechanism ◽  
Direct Reaction ◽  
Exchange Reactions ◽  
Protease Inhibition ◽  
Biological Media

<div>There have been significant advances in the biological use of hypervalent selenium and tellurium compounds as cysteine protease inhibitors over the recent past. However, the full understanding of their reaction mechanisms in aqueous medium and the mechanism of cysteine proteases inhibition is still elusive. Kinetic studies suggest an irreversible inhibition mechanism, which was explained by forming a covalent bond between the enzyme sulfhydryl group and the chalcogen atom at its hypervalent state (+4). However, it is still unclear the active form of the inhibitor present in the aqueous biological media. To uncover this question, we performed a theoretical investigation using density functional theory (DFT). This study investigated chloride ligand exchange reactions by oxygen and sulfur nucleophiles on hypervalent selenium and tellurium compounds. All tetra- and tri-coordinate chalcogen compounds and distinct protonation states of the nucleophiles were considered, totaling 34 unique species, 7</div><div>nucleophiles and 155 free energies rections. We discovered that chloride is easily replaced by a nonprotonated nucleophile (SH<sup>–</sup> or OH<sup>– </sup>) in R<sub>2</sub>SeCl<sub>2</sub> . We also found that</div><div>tri-coordinate species are more stable than their tetra-coordinate counterparts, with selenoxide (R<sub>2</sub>SeO) protonation being strongly exergonic in acid pH. These results suggest that the protonated selenoxide (R<sub>2</sub>SeOH<sup>+</sup>) is the most probable active chemical species in biological media. The computed energetic profiles paint a possible picture for the selenurane activity, with successive exergonic steps leading to a covalent inhibition of thiol dependent enzymes, like cysteine proteases. A second less exergonic pathway has also been uncovered, with a direct reaction to chalcogenonium cation (R<sub>2</sub>SeCl<sup>+</sup>) as the inhibition step. The trends observed for the telluranes were similar, albeit with</div><div>more exergonic reactions and a stronger trend to form bonds with oxygen species then selenuranes.</div><div><br></div>

On-the-Fly Determination of Active Region Centers in Adaptive-Partitioning QM/MM

2020 ◽  
Author(s):  
Zenghui Yang
Keyword(s):  
Quantum Mechanics ◽  
Active Region ◽  
Molecular Mechanics ◽  
Active Regions ◽  
Available Energy ◽  
Adaptive Partitioning ◽  
Different Levels

Quantum mechanics/molecular mechanics (QM/MM) methods partition the system into active and environmental regions and treat them with different levels of theory, achieving accuracy and efficiency at the same time. Adaptive-partitioning (AP) QM/MM methods allow on-the-fly changes to the QM/MM partitioning of the system. Many of the available energy-based AP-QM/MM methods partition the system according to distances to pre-chosen centers of active regions. For such AP-QM/MM methods, I develop an adaptive-center (AC) method that allows on-the-fly determination of the centers of active regions according to general geometrical or potential-related criteria, extending the range of application of energy-based AP-QM/MM methods to systems where active regions may occur or vanish during the simulation.

A Conserved Asparagine in a Ubiquitin Conjugating Enzyme Positions the Substrate for Nucleophilic Attack

2018 ◽  
Author(s):  
Walker M. Jones ◽  
Aaron G. Davis ◽  
R. Hunter Wilson ◽  
Katherine L. Elliott ◽  
Isaiah Sumner
Keyword(s):  
Molecular Dynamics ◽  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Reaction Rates ◽  
Nucleophilic Attack ◽  
Classical Molecular Dynamics ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

We present classical molecular dynamics (MD), Born-Oppenheimer molecular dynamics (BOMD), and hybrid quantum mechanics/molecular mechanics (QM/MM) data. MD was performed using the GPU accelerated pmemd module of the AMBER14MD package. BOMD was performed using CP2K version 2.6. The reaction rates in BOMD were accelerated using the Metadynamics method. QM/MM was performed using ONIOM in the Gaussian09 suite of programs. Relevant input files for BOMD and QM/MM are available.

scholarly journals A Novel Cysteine Protease Inhibitor of Naegleria fowleri That Is Specifically Expressed during Encystation and at Mature Cysts

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 388
Author(s):  
Hương Giang Lê ◽  
A-Jeong Ham ◽  
Jung-Mi Kang ◽  
Tuấn Cường Võ ◽  
Haung Naw ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Cysteine Protease ◽  
Expression Profiles ◽  
Critical Role ◽  
Cyst Formation ◽  
Cysteine Proteases ◽  
Cysteine Protease Inhibitor ◽  
Naegleria Fowleri ◽  
Nægleria Fowleri ◽  
Cystatin Family

Naegleria fowleri is a free-living amoeba that is ubiquitous in diverse natural environments. It causes a fatal brain infection in humans known as primary amoebic meningoencephalitis. Despite the medical importance of the parasitic disease, there is a great lack of knowledge about the biology and pathogenicity of N. fowleri. In this study, we identified and characterized a novel cysteine protease inhibitor of N. fowleri (NfCPI). NfCPI is a typical cysteine protease inhibitor belonging to the cystatin family with a Gln-Val-Val-Ala-Gly (QVVAG) motif, a characteristic motif conserved in the cystatin family of proteins. Bacterially expressed recombinant NfCPI has a dimeric structure and exhibits inhibitory activity against several cysteine proteases including cathespin Bs of N. fowleri at a broad range of pH values. Expression profiles of nfcpi revealed that the gene was highly expressed during encystation and cyst of the amoeba. Western blot and immunofluorescence assays also support its high level of expression in cysts. These findings collectively suggest that NfCPI may play a critical role in encystation or cyst formation of N. fowleri by regulating cysteine proteases that may mediate encystation or mature cyst formation of the amoeba. More comprehensive studies to investigate the roles of NfCPI in encystation and its target proteases are necessary to elucidate the regulatory mechanism and the biological significance of NfCPI.

Automated Parametrization of Biomolecular Force Fields from Quantum Mechanics/Molecular Mechanics (QM/MM) Simulations through Force Matching

2007 ◽  
Vol 3 (2) ◽  
pp. 628-639 ◽  
Author(s):  
Patrick Maurer ◽  
Alessandro Laio ◽  
Håkan W. Hugosson ◽  
Maria Carola Colombo ◽  
Ursula Rothlisberger
Keyword(s):  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Force Fields ◽  
Force Matching
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