Serine proteases: An ab initio molecular dynamics study

  title={Serine proteases: An ab initio molecular dynamics study},
  author={Laura De Santis and Paolo Carloni},
  journal={Proteins: Structure},
In serine proteases (SPs), the H‐bond between His57 and Asp102 and that between Gly193 and the transition state intermediate play a crucial role in enzymatic function. To shed light on the nature of these interactions, we have carried out ab initio molecular dynamics simulations on complexes representing adducts between the reaction intermediate and elastase (one protein belonging to the SP family). Our calculations indicate the presence of a low‐barrier H‐bond between His57 and Asp102, in… 

Is there a weak H‐bond → LBHB transition on tetrahedral complex formation in serine proteases?

The hydrogen bond in both the free enzyme and in the enzyme‐inhibitor TC is a strong ionic asymmetric one‐well hydrogen bond, in contrast to a previous suggestion that it is a weak H‐bond in the former and a double‐well LBHB in the latter.

NADH interactions with WT‐ and S94A‐acyl carrier protein reductase from Mycobacterium tuberculosis: An ab initio study

The authors' calculations suggest that the water‐mediated H‐bond interactions between Ser94 side chain and NADH, present in WT InhA X‐ray structure, can be lost during the dynamics.

Proton Transfer at Metal Sites in Proteins Studied by Quantum Mechanical Free-Energy Perturbations.

This work studies three proton-transfer reactions in two proteins and shows that these reactions strongly depend on the electrostatic interactions with the surrounding protein and solvent, because there is a large change in the dipole moment of the active site.

Theoretical study of structure of catalytic copper site in nitrite reductase

The catalytic copper site in nitrite reductase contains a Cu2+ ion bound to three histidine (His) ligands and a solvent molecule. Sites from various sources show a conspicuous variation in the

Ab initio molecular dynamics studies on HIV‐1 reverse transcriptase triphosphate binding site: Implications for nucleoside‐analog drug resistance

  • F. AlberP. Carloni
  • Chemistry, Biology
    Protein science : a publication of the Protein Society
  • 2000
Quantum‐chemical methods are used to shed light on the functional role of residues involved in the resistance of HIV‐1 reverse transcriptase against nucleoside‐analog drugs. Ab initio molecular

Accurate prediction of protonation state as a prerequisite for reliable MM‐PB(GB)SA binding free energy calculations of HIV‐1 protease inhibitors

It is found that the inclusion of explicit water molecules may offer a slight advantage in reproducing absolute binding free energies while the use of the Generalized Born approximation significantly affects the accuracy of the calculated binding affinities.

Comparative Theoretical Study of the Ring-Opening Polymerization of Caprolactam vs Caprolactone Using QM/MM Methods

A decisive difference is identified in the accessibility of the two substrates in the ring-opening to the respective acyl enzyme complex as the attack of e-caprolactam is hindered because of an energetically disfavored proton tumbling.



Importance of hydrogen-bond formation in stabilizing the transition state of subtilisin

Enrichment methods are described which greatly facilitate the isolation of mutant sequences and depend upon the introduction or elimination of a unique and silent restriction site near the site of mutagenesis.

Ab initio molecular dynamics studies of a synthetic biomimetic model of galactose oxidase

Very recently, highly efficient biomimetic models of the mononuclear copper enzyme galactose oxidase were synthesized which are able to reproduce the structural, spectroscopic, and functional

Evidence for a tetrahedral intermediate complex during serpin-proteinase interactions.

How do serine proteases really work?

It is argued that serine proteases and other enzymes work by providing electrostatic complementarity to the changes in charge distribution occurring during the reactions they catalyze.

Free energy perturbation calculations on binding and catalysis after mutating Asn 155 in subtilisin

A new approach called the free-energy pertubation method, which uses statistical mechanics and molecular dynamics can often be used for quantitative calculation of free energy differences, is applied to calculate the differential free energy of binding and freeEnergy of activation for catalysis of a tripeptide substrate by native subtilisin and a subtILisin mutant.

A low-barrier hydrogen bond in the catalytic triad of serine proteases.

Spectroscopic properties of chymotrypsin and model compounds indicate that a low-barrier hydrogen bond participates in the mechanism of serine protease action, supported by the chemical shift of this proton, the deuterium isotope effect on thechemical shift, and the properties of hydrogen-bonded model compounds in organic solvents.

Site-directed mutagenesis and the role of the oxyanion hole in subtilisin.

Oligonucleotide-directed mutagenesis was used to investigate the nature of transition state stabilization in the catalytic mechanism of the serine protease, subtilisin BPN'. The gene for this

Semiquantitative calculations of catalytic free energies in genetically modified enzymes.

The calculated changes in catalytic free energies are almost entirely due to the electrostatic interaction between the enzyme-water system and the charges of the reacting system, which supports the idea that the electro static free energy associated with the changes of charges ofThe reacting system is the key factor in enzyme catalysis.

Low-barrier hydrogen bonds and enzymic catalysis.

Several examples of enzymatic reactions that appear to use this principle are presented, and a weak hydrogen bond in the enzyme-substrate complex in which the pKa's do not match can become a strong, low-barrier one if the p Ka's become matched in the transition state or enzyme-intermediate complex.

On low-barrier hydrogen bonds and enzyme catalysis.

Although we agree that hydrogen bonds are important in enzyme catalysis, we disagree with the contention of Cleland and Kreevoy (1) and Frey et al. (2) that "lowbarrier hydrogen bonds" (LBHBs) can