Quantum Mechanical Prediction of Dissociation Constants for Thiazol-2-imine Derivatives.

As weak acids or bases, in solution, drug molecules are in either their ionized or nonionized states. A high degree of ionization is essential for good water solubility of a drug molecule and is required for drug-receptor interactions, whereas the nonionized form improves a drug's lipophilicity, allowing the ligand to cross the cell membrane. The penetration of a drug ligand through cell membranes is mainly governed by the p of the drug molecule and the membrane environment.

Unexplored Vinylic-Substituted 5-Benzylidenethiazolidine-2,4-diones: Synthesis and DFT/NMR Stereochemical Assignment.

By exploring an efficient and versatile method for the 6-functionalization of its scaffold, we investigated the opening of a new chemical space around benzylidenethiazolidine-2,4-dione (BTZD). The 6-chloro- and 6-formyl BTZD obtained in two steps starting from 5-lithioTZD were selected as key intermediates and involved in a Pd-catalyzed cross-coupling or Wittig olefination. A variety of aryl, heteroaryl, or alkenyl substituents was successfully introduced on the vinylic position of BTZD, and particular attention was paid to elucidate the stereochemistry of the benzylidene derivatives by using a combined DFT/NMR study.

Molecular Mechanism of Protein Arginine Deiminase 2: A Study Involving Multiple Microsecond Long Molecular Dynamics Simulations.

Peptidylarginine deiminase 2 (PAD2) is a Ca-dependent enzyme that catalyzes the conversion of protein arginine residues to citrulline. This kind of structural modification in histone molecules may affect gene regulation, leading to effects that may trigger several diseases, including breast cancer, which makes PAD2 an attractive target for anticancer drug development. To design new effective inhibitors to control activation of PAD2, improving our understanding of the molecular mechanisms of PAD2 using up-to-date computational techniques is essential.

Impact of Deamidation on the Structure and Function of Antiapoptotic Bcl-x.

Bcl-x is an antiapoptotic mitochondrial trans-membrane protein, which is known to play a crucial role in the survival of tumor cells. The deamidation of Bcl-x is a pivotal switch that regulates its biological function. The potential impact of deamidation on the structure and dynamics of Bcl-x is directly linked to the intrinsically disordered region (IDR), which is the main site for post-translational modifications (PTMs).

Using Atomic Charges to Describe the p of Carboxylic Acids.

In this study, we present an accurate protocol for the fast prediction of p's of carboxylic acids based on the linear relationship between computed atomic charges of the anionic form of the carboxylate fragment and their experimental p values. Five charge descriptors, three charge models, three solvent models, gas-phase calculations, several DFT methods (a combination of eight DFT functionals and fifteen basis sets), and four different semiempirical approaches were tested. Among those, the best combination to reproduce experimental p's is to compute the natural population analysis atomic charge using the solvation model based on density model at the M06L/6-311G(d,p) level of theory and selecting the maximum atomic charge on the carboxylic oxygen atoms ( = 0.

Elucidation of the atroposelectivity in the synthesis of axially chiral thiohydantoin derivatives.

Recently, Sarigul and Dogan have synthesized a number of enantiomerically enriched axially chiral atropoisomeric 2-thiohydantoins by the reaction of l-amino acid ester salts and o-aryl isothiocyanates in the presence of triethyl amine (TEA) in dichloromethane. The non-axially chiral derivative 5-methyl-3-phenyl-2-thiohydantoin gave a racemic product whereas the axially chiral 5-methyl-3-o-bromophenyl-2-thiohydantoin was less prone to racemize at C5 of the heterocyclic ring. In this study, we present a computational study (M06-2X/6-311+G(d,p) for C, H, O, N and S; M06-2X/6-311++G(3df,3pd) for Br) in order to propose plausible mechanisms for the racemization and cyclization steps for 2-thiohydantoin derivatives.

Dendrigraft of Poly-l-lysine as a Promising Candidate To Reverse Heparin-based Anticoagulants in Clinical Settings.

By using a combination of experimental and computational experiments, we demonstrated that a second-generation dendrigraft of poly-l-lysine neutralizes the anticoagulant activity of unfractionated heparin, low-molecular-weight heparin, and fondaparinux more efficiently than protamine does in human plasma, making this synthetic polymer a promising surrogate of this problematic protein in clinical settings.

Semi-Empirical Born-Oppenheimer Molecular Dynamics (SEBOMD) within the Amber Biomolecular Package.

Semi-empirical quantum methods from the neglect of differential diatomic overlap (NDDO) family such as MNDO, AM1, or PM3 are fast albeit approximate quantum methods. By combining them with linear scaling methods like the divide & conquer (D&C) method, it is possible to quickly evaluate the energy of systems containing hundreds to thousands of atoms. We here present our implementation in the Amber biomolecular package of a SEBOMD module that provides a way to run semi-empirical Born-Oppenheimer molecular dynamics.

Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor.

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands.

Biotinylation enhances the anticancer effects of 15d‑PGJ2 against breast cancer cells.

15-Deoxy-∆12,14-prostaglandin J2 (15d‑PGJ2) is a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that displays anticancer activity. Various studies have indicated that the effects of 15d‑PGJ2 are due to both PPARγ-dependent and -independent mechanisms. In the present study, we examined the effects of a biotinylated form of 15d‑PGJ2 (b‑15d‑PGJ2) on hormone-dependent MCF‑7 and triple‑negative MDA‑MB‑231 breast cancer cell lines.

Digitizing Poly-l-lysine Dendrigrafts: From Experimental Data to Molecular Dynamics Simulations.

Despite the growing use of poly-l-lysine dendrigrafts in biomedical applications, a deeper understanding of the molecular level properties of these macromolecules is missing. Herein, we report a simple methodology for the construction of three-dimensional structures of poly-l-lysine dendrigrafts and the subsequent investigation of their structural features using microsecond molecular dynamics simulations. This methodology relies on the encoding of the polymers' experimental characterizations (i.

Assessing protein-ligand binding modes with computational tools: the case of PDE4B.

In a first step in the discovery of novel potent inhibitor structures for the PDE4B family with limited side effects, we present a protocol to rank newly designed molecules through the estimation of their IC[Formula: see text] values. Our protocol is based on reproducing the linear relationship between the logarithm of experimental IC[Formula: see text] values [[Formula: see text](IC[Formula: see text])] and their calculated binding free energies ([Formula: see text]). From 13 known PDE4B inhibitors, we show here that (1) binding free energies obtained after a docking process by AutoDock are not accurate enough to reproduce this linear relationship; (2) MM-GB/SA post-processing of molecular dynamics (MD) trajectories of the top ranked AutoDock pose improves the linear relationship; (3) by taking into account all representative structures obtained by AutoDock and by averaging MM-GB/SA computations on a series of 40 independent MD trajectories, a linear relationship between [Formula: see text](IC[Formula: see text]) and the lowest [Formula: see text] is achieved with [Formula: see text].

Molecular dynamics simulations of apo, holo, and inactivator bound GABA-at reveal the role of active site residues in PLP dependent enzymes.

The pyridoxal 5-phosphate (PLP) cofactor is a significant organic molecule in medicinal chemistry. It is often found covalently bound to lysine residues in proteins to form PLP dependent enzymes. An example of this family of PLP dependent enzymes is γ-aminobutyric acid aminotransferase (GABA-AT) which is responsible for the degradation of the neurotransmitter GABA.

Why does Asn71 deamidate faster than Asn15 in the enzyme triosephosphate isomerase? Answers from microsecond molecular dynamics simulation and QM/MM free energy calculations.

Deamidation is the uncatalyzed process by which asparagine or glutamine can be transformed into aspartic acid or glutamic acid, respectively. In its active homodimeric form, mammalian triosephosphate isomerase (TPI) contains two deamidation sites per monomer. Experimental evidence shows that the primary deamidation site (Asn71-Gly72) deamidates faster than the secondary deamidation site (Asn15-Gly16).

Hydration Effect on Amide I Infrared Bands in Water: An Interpretation Based on an Interaction Energy Decomposition Scheme.

The sensitivity of some infrared bands to the local environment can be exploited to shed light on the structure and the dynamics of biological systems. In particular, the amide I band, which is specifically related to vibrations within the peptide bonds, can give information on the ternary structure of proteins, and can be used as a probe of energy transfer. In this work, we propose a model to quantitatively interpret the frequency shift on the amide I band of a model peptide induced by the formation of hydrogen bonds in the first solvation shell.

Rationalization of the pKa values of alcohols and thiols using atomic charge descriptors and its application to the prediction of amino acid pKa's.

In a first step toward the development of an efficient and accurate protocol to estimate amino acids' pKa's in proteins, we present in this work how to reproduce the pKa's of alcohol and thiol based residues (namely tyrosine, serine, and cysteine) in aqueous solution from the knowledge of the experimental pKa's of phenols, alcohols, and thiols. Our protocol is based on the linear relationship between computed atomic charges of the anionic form of the molecules (being either phenolates, alkoxides, or thiolates) and their respective experimental pKa values. It is tested with different environment approaches (gas phase or continuum solvent-based approaches), with five distinct atomic charge models (Mulliken, Löwdin, NPA, Merz-Kollman, and CHelpG), and with nine different DFT functionals combined with 16 different basis sets.

Water interactions with hydrophobic groups: assessment and recalibration of semiempirical molecular orbital methods.

In this work, we present a study of the ability of different semiempirical methods to describe intermolecular interactions in water solution. In particular, we focus on methods based on the Neglect of Diatomic Differential Overlap approximation. Significant improvements of these methods have been reported in the literature in the past years regarding the description of non-covalent interactions.

Vibrational energy relaxation of the amide I mode of N-methylacetamide in D₂O studied through Born-Oppenheimer molecular dynamics.

The vibrational relaxation of the amide I mode of deuterated N-methylacetamide in D2O solution is studied through nonequilibrium simulations using the semiempirical Born-Oppenheimer molecular dynamics (SEBOMD) approach to describe the whole solute-solvent system. Relaxation pathways and lifetimes are determined using the instantaneous normal mode (INM) analysis. The relaxation of the amide I mode is characterized by three different time scales; most of the excess energy (80%) is redistributed through intramolecular vibrational energy redistribution processes, with a smaller contribution (20%) of intermolecular energy flowing into the solvent.

Initiation of the reaction of deamidation in triosephosphate isomerase: investigations by means of molecular dynamics simulations.

Deamidation of asparagine is the spontaneous degradation of this residue into aspartic acid. The kinetics of this slow reaction is mainly dependent on the nature of the adjacent amino acid that follows asparagine in a peptide or protein primary sequence. In the homodimer triosephosphate isomerase (TPI), there are two main deamidation sites per subunit: Asn15-Gly16 and Asn71-Gly72 for which deamidation dynamics are known to be interrelated.

Peptide binding to β-cyclodextrins: structure, dynamics, energetics, and electronic effects.

Peptide-cyclodextrin and protein-cyclodextrin host-guest complexes are becoming more and more important for industrial applications, in particular in the fields of pharmaceutical and food chemistry. They have already deserved many experimental investigations although the effect of complex formation in terms of peptide (or protein) structure is not well-known yet. Theoretical calculations represent a unique tool to analyze such effects, and with this aim we have carried out in the present investigation molecular dynamics simulations and combined quantum mechanics-molecular mechanics calculations.

Importance of Polarization and Charge Transfer Effects to Model the Infrared Spectra of Peptides in Solution.

We present a study of the infrared spectrum of N-methyl acetamide (NMA) performed by using molecular dynamics (MD) with a quantum electronic Hamiltonian. A recently developed method, based on the Born-Oppenheimer approximation and on a semiempirical level of quantum chemistry (SEBOMD), is employed. We focus on the solvent effect on the infrared spectrum of the solute, on its geometry, and on its electrostatic properties.

X-ray, ESR, and quantum mechanics studies unravel a spin well in the cofactor-less urate oxidase.

Urate oxidase (EC 1.7.3.

Computer simulation of reactions in beta-cyclodextrin molecular reactors: transition state recognition.

Cyclodextrins have attracted much interest in recent years because of their potential use as molecular reactors allowing organic reactions in aqueous solution. To better understand their effect on reaction mechanisms, we have carried out a computational study of a prototypical process (neutral ester hydrolysis) in a beta-cyclodextrin (beta-CD). Two models have been used for the reactor.

Intrinsic reactivity of uric acid with dioxygen: Towards the elucidation of the catalytic mechanism of urate oxidase.

Urate oxidase catalyzes the transformation of uric acid in 5-hydroxyisourate, an unstable compound which is latter decomposed into allantoïn. Crystallographic data have shown that urate oxidase binds a dianion urate species deprotonated in N3 and N7, while kinetics experiments have highlighted the existence of several intermediates during catalysis. We have employed a quantum mechanical approach to analyze why urate oxidase is selective for one particular dianion and to explore all possible reaction pathways for the oxidation of one uric acid species by molecular dioxygen in presence of water.

Deamidation of asparagine residues: direct hydrolysis versus succinimide-mediated deamidation mechanisms.

Quantum chemical calculations are reported to provide new insights on plausible mechanisms leading to the deamidation of asparagine residues in proteins and peptides. Direct hydrolysis to aspartic acid and several succinimide-mediated mechanisms have been described. The catalytic effect of water molecules has been explicitly analyzed.