Fortuitous Correlations in Molecular Dynamics Simulations: Their Harmful Influence on the Probability Distributions of the Main Principal Components.

Nonsense correlations frequently develop between independent random variables that evolve with time. Therefore, it is not surprising that they appear between the components of vectors carrying out multidimensional random walks, such as those describing the trajectories of biomolecules in molecular dynamics simulations. The existence of these correlations does not imply in itself a problem.

The dynamics of the flavin, NADPH, and active site loops determine the mechanism of activation of class B flavin-dependent monooxygenases.

Flavin-dependent monooxygenases (FMOs) constitute a diverse enzyme family that catalyzes crucial hydroxylation, epoxidation, and Baeyer-Villiger reactions across various metabolic pathways in all domains of life. Due to the intricate nature of this enzyme family's mechanisms, some aspects of their functioning remain unknown. Here, we present the results of molecular dynamics computations, supplemented by a bioinformatics analysis, that clarify the early stages of their catalytic cycle.

Dynamics and Function of sRNA/mRNAs Under the Scrutiny of Computational Simulation Methods.

Molecular dynamics simulations have proved extremely useful in investigating the functioning of proteins with atomic-scale resolution. Many applications to the study of RNA also exist, and their number increases by the day. However, implementing MD simulations for RNA molecules in solution faces challenges that the MD practitioner must be aware of for the appropriate use of this tool.

On the Uses of PCA to Characterise Molecular Dynamics Simulations of Biological Macromolecules: Basics and Tips for an Effective Use.

Principal Component Analysis (PCA) is a procedure widely used to examine data collected from molecular dynamics simulations of biological macromolecules. It allows for greatly reducing the dimensionality of their configurational space, facilitating further qualitative and quantitative analysis. Its simplicity and relatively low computational cost explain its extended use.

Recognition and Binding of RsmE to an AGGAC Motif of RsmZ: Insights from Molecular Dynamics Simulations.

CsrA/RsmE is a post-transcriptional regulator protein widely distributed in bacteria. It impedes the expression of target mRNAs by attaching their 5' untranslated region. The translation is restored by small, noncoding RNAs that sequester CsrA/RsmE acting as sponges.

Ion Selectivity in P2X Receptors: A Comparison between hP2X3 and zfP2X4.

Charge discrimination in P2X receptors occurs in two stages. The first stage takes place in the extracellular vestibule. The second one happens as the ions travel across the pore.

Positively Charged Residues in the Head Domain of P2X4 Receptors Assist the Binding of ATP.

P2X receptors are a family of trimeric cationic channels located in the membrane of mammalian cells. They open in response to the binding of ATP. The differences between the closed and open structures have been described in detail for some members of the family.

Charge Discrimination in P2X Receptors Occurs in Two Consecutive Stages.

P2X receptors are a group of trimeric cationic channels that are activated by adenosine 5'-triphosphate. They perform critical roles in the membranes of mammalian cells, and their improper functioning is associated with numerous diseases. Despite the vast amount of research devoted to them, several aspects of their operation are currently unclear, including the causes of their charge selectivity.

Molecular Dynamics Simulations of Substrate Release from Trypanosoma cruzi UDP-Galactopyranose Mutase.

The enzyme UDP-galactopyranose mutase (UGM) represents a promising drug target for the treatment of infections with Trypanosoma cruzi. We have computed the Potential of Mean Force for the release of UDP-galactopyranose from UGM, using Umbrella Sampling simulations. The simulations revealed the conformational changes that both substrate and enzyme undergo during the process.

Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase.

Galactose is an abundant monosaccharide found exclusively in mammals as galactopyranose (Gal p), the six-membered ring form of this sugar. In contrast, galactose appears in many pathogenic microorganisms as the five-membered ring form, galactofuranose (Gal f). Gal f biosynthesis begins with the conversion of UDP-Gal p to UDP-Gal f catalyzed by the flavoenzyme UDP-galactopyranose mutase (UGM).

Consistent Principal Component Modes from Molecular Dynamics Simulations of Proteins.

Principal component analysis is a technique widely used for studying the movements of proteins using data collected from molecular dynamics simulations. In spite of its extensive use, the technique has a serious drawback: equivalent simulations do not afford the same PC-modes. In this article, we show that concatenating equivalent trajectories and calculating the PC-modes from the concatenated one significantly enhances the reproducibility of the results.

The Dynamic Behavior of the P2X Ion Channel in the Closed Conformation.

We present the results of a detailed molecular dynamics study of the closed form of the P2X receptor. The fluctuations observed in the simulations were compared with the changes that occur in the transition from the closed to the open structure. To get further insight on the opening mechanism, the actual displacements were decomposed into interchain motions and intrachain deformations.

Theoretical Insights into the Reaction and Inhibition Mechanism of Metal-Independent Retaining Glycosyltransferase Responsible for Mycothiol Biosynthesis.

Understanding enzymatic reactions with atomic resolution has proven in recent years to be of tremendous interest for biochemical research, and thus, the use of QM/MM methods for the study of reaction mechanisms is experiencing a continuous growth. Glycosyltransferases (GTs) catalyze the formation of glycosidic bonds, and are important for many biotechnological purposes, including drug targeting. Their reaction product may result with only one of the two possible stereochemical outcomes for the reacting anomeric center, and therefore, they are classified as either inverting or retaining GTs.

New insights into the meaning and usefulness of principal component analysis of concatenated trajectories.

A comparison between different conformations of a given protein, relating both structure and dynamics, can be performed in terms of combined principal component analysis (combined-PCA). To that end, a trajectory is obtained by concatenating molecular dynamics trajectories of the individual conformations under comparison. Then, the principal components are calculated by diagonalizing the correlation matrix of the concatenated trajectory.

QM/MM molecular dynamics study of the galactopyranose → galactofuranose reaction catalysed by Trypanosoma cruzi UDP-galactopyranose mutase.

The enzyme UDP-Galactopyranose Mutase (UGM) catalyses the conversion of galactopyranose into galactofuranose. It is known to be critical for the survival and proliferation of several pathogenic agents, both prokaryotic and eukaryotic. Among them is Trypanosoma cruzi, the parasite responsible for Chagas' disease.

Unraveling the differences of the hydrolytic activity of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase: a quantum mechanics-molecular mechanics modeling study.

Chagas' disease, also known as American trypanosomiasis, is a lethal, chronic disease that currently affects more than 10 million people in Central and South America. The trans-sialidase from Trypanosoma cruzi (T. cruzi, TcTS) is a crucial enzyme for the survival of this parasite: sialic acids from the host are transferred to the cell surface glycoproteins of the trypanosome, thereby evading the host's immune system.

Free-energy computations identify the mutations required to confer trans-sialidase activity into Trypanosoma rangeli sialidase.

Trypanosoma rangeli's sialidase (TrSA) and Trypanosoma cruzi's trans-sialidase (TcTS) are members of the glycoside hydrolase family 33 (GH-33). They share 70% of sequence identity and their crystallographic Cα RMSD is 0.59 Å.

Free energy study of the catalytic mechanism of Trypanosoma cruzi trans-sialidase. From the Michaelis complex to the covalent intermediate.

Trypanosoma cruzi trans-sialidase (TcTS) is a crucial enzyme for the infection of Trypanosoma cruzi, the protozoa responsible for Chagas' disease in humans. It catalyzes the transfer of sialic acids from the host's glycoconjugates to the parasite's glycoconjugates. Based on kinetic isotope effect (KIE) studies, a strong nucleophilic participation at the transition state could be determined, and recently, elaborate experiments used 2-deoxy-2,3-difluorosialic acid as substrate and were able to trap a long-lived covalent intermediate (CI) during the catalytic mechanism.

Proton transfer facilitated by ligand binding. An energetic analysis of the catalytic mechanism of Trypanosoma cruzi trans-sialidase.

Trans-sialidase is a crucial enzyme for the infection of Trypanosoma cruzi, the protozoa responsible for Chagas' disease in humans. This enzyme catalyzes the transfer of sialic acids from mammalian host cells to parasitic cell surfaces in order to mask the infection from the host's immune system. It represents a promising target for the development of therapeutics to treat the disease and has been subject of extensive structural studies.