Utility of Brownian dynamics simulations in chemistry and biology: A comprehensive review.

Brownian dynamics (BD) simulations, a powerful computer simulation tool that has gained significant attraction in investigating the intricate dynamics of chemical and biological systems. By meticulously modeling the diffusive motion of molecules and their intricate interactions, BD simulations offer invaluable insights into a diverse array of phenomena, including reaction kinetics, molecular transport, and biomolecular association. This comprehensive review delves into the utility of BD simulations within the realms of chemistry and biology.

Competitive Interaction of the SGFRKMAF Peptide with 3CLpro Dimerization Intermediates: A Brownian Dynamics Investigation.

The SGFRKMAF peptide is known to inhibit the dimerization of 3CLpro monomers, which is essential for SARS-CoV-2 replication. The mechanism behind this, however, is largely unknown. In this work, we used Brownian dynamics simulations to compare and contrast 3CLpro monomer-monomer interactions and 3CLpro monomer-SGFRKMAF peptide interactions.

Disruption of 3CLpro protease self-association by short peptides as a potential route to broad spectrum coronavirus inhibitors.

Coronaviruses have posed a persistent threat to human health over the last two decades. Despite the accumulated knowledge about coronavirus-related pathogens, development of an effective treatment for its new variant COVID-19 is highly challenging. For the highly-conserved and main coronavirus protease 3CLpro, dimerization is known to be essential for its catalytic activity and thereby for virus proliferation.

Potential Breast Anticancer Drug Targets Revealed by Differential Gene Regulatory Network Analysis and Molecular Docking: Neoadjuvant Docetaxel Drug as a Case Study.

Understanding gene-gene interaction and its causal relationship to protein-protein interaction is a viable route for understanding drug action at the genetic level, which is largely hindered by inability to robustly map gene regulatory networks. Here, we use biological prior knowledge of family-to-family gene interactions available in the KEGG database to reveal individual gene-to-gene interaction networks that underlie the gene expression profiles of 2 cell line data sets, sensitive and resistive to neoadjuvant docetaxel breast anticancer drug. Comparison of the topology of the 2 networks revealed that the resistant network is highly connected with 2 large domains of connectivity: one in which the RAF1 and MAP2K2 genes form hubs of connectivity and another in which the RAS gene is highly connected.

The impact of viral RNA on the association free energies of capsid protein assembly: bacteriophage MS2 as a case study.

A large number of single-stranded RNA viruses assemble their capsid and their genomic material simultaneously. The RNA viral genome plays multiple roles in this process that are currently only partly understood. In this work, we investigated the thermodynamic basis of the role of viral RNA on the assembly of capsid proteins.

Reactivation of mutant p53: Constraints on mechanism highlighted by principal component analysis of the DNA binding domain.

Most p53 mutations associated with cancer are located in its DNA binding domain (DBD). Many structures (X-ray and NMR) of this domain are available in the protein data bank (PDB) and a vast conformational heterogeneity characterizes the various free and complexed states. The major difference between the apo and the holo-complexed states appears to lie in the L1 loop.

Recognition Dynamics of p53 and MDM2: Implications for Peptide Design.

Peptides that inhibit MDM2 and attenuate MDM2-p53 interactions, thus activating p53, are currently being pursued as anticancer drug leads for tumors harboring wild type p53. The thermodynamic determinants of peptide-MDM2 interactions have been extensively studied. However, a detailed understanding of the dynamics that underlie these interactions is largely missing.

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2.

The interaction of p53 and MDM2 is modulated by the phosphorylation of p53. This mechanism is key to activating p53, yet its molecular determinants are not fully understood. To study the spatiotemporal characteristics of this molecular process we carried out Brownian dynamics simulations of the interactions of the MDM2 protein with a p53 peptide in its wild type state and when phosphorylated at Thr18 (pThr18) and Ser20 (pSer20).

On the origin of the stereoselective affinity of Nutlin-3 geometrical isomers for the MDM2 protein.

The stereoselective affinity of small-molecule binding to proteins is typically broadly explained in terms of the thermodynamics of the final bound complex. Using Brownian dynamics simulations, we show that the preferential binding of the MDM2 protein to the geometrical isomers of Nutlin-3, an effective anticancer lead that works by inhibiting the interaction between the proteins p53 and MDM2, can be explained by kinetic arguments related to the formation of the MDM2:Nutlin-3 encounter complex. This is a diffusively bound state that forms prior to the final bound complex.

On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: a Brownian dynamics study.

The interaction of p53 with its regulators MDM2 and MDMX plays a major role in regulating the cell cycle. Inhibition of this interaction has become an important therapeutic strategy in oncology. Although MDM2 and MDMX share a very high degree of sequence/structural similarity, the small-molecule inhibitor nutlin appears to be an efficient inhibitor only of the p53-MDM2 interaction.

Peptide inhibitors of viral assembly: a novel route to broad-spectrum antivirals.

We investigated the potential of small peptide segments to function as broad-spectrum antiviral drug leads. We extracted the α-helical peptide segments that share common secondary-structure environments in the capsid protein-protein interfaces of three unrelated virus classes (PRD1-like, HK97-like, and BTV-like) that encompass different levels of pathogenicity to humans, animals, and plants. The potential for the binding of these peptides to the individual capsid proteins was then investigated using blind docking simulations.

Characterization of the Ligand Receptor Encounter Complex and Its Potential for in Silico Kinetics-Based Drug Development.

The study of drug-receptor interactions has largely been framed in terms of the equilibrium thermodynamic binding affinity, an in vitro measure of the stability of the drug-receptor complex that is commonly used as a proxy measure of in vivo biological activity. In response to the growing realization of the importance of binding kinetics to in vivo drug activity we present a computational methodology for the kinetic characterization of drug-receptor interactions in terms of the encounter complex. Using trajectory data from multiple Brownian dynamics simulations of ligand diffusion, we derive the spatial density of the ligand around the receptor and show how it can be quantitatively partitioned into different basins of attraction.

On the origin of order in the genome organization of ssRNA viruses.

Single-stranded RNA (ssRNA) viruses form a major class that includes important human, animal, and plant pathogens. While the principles underlying the structures of their protein capsids are generally well understood, much less is known about the organization of their encapsulated genomic RNAs. Cryo-electron microscopy and x-ray crystallography have revealed striking evidence of order in the packaged genomes of a number of ssRNA viruses.

The impact of viral RNA on the association rates of capsid protein assembly: bacteriophage MS2 as a case study.

A large number of single-stranded RNA viruses, which form a major class of all viruses, co-assemble their protein container and their genomic material. The multiple roles of the viral genome in this process are presently only partly understood. Recent experimental results indicate that RNA, in addition to its function as a repository for genetic information, could play important functional roles during the assembly of the viral protein containers.

Bio3d: an R package for the comparative analysis of protein structures.

Unlabelled: An automated procedure for the analysis of homologous protein structures has been developed. The method facilitates the characterization of internal conformational differences and inter-conformer relationships and provides a framework for the analysis of protein structural evolution. The method is implemented in bio3d, an R package for the exploratory analysis of structure and sequence data.

The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA.

A multivariate analysis of the backbone and sugar torsion angles of dinucleotide fragments was used to construct a 3D principal conformational subspace (PCS) of DNA duplex crystal structures. The potential energy surface (PES) within the PCS was mapped for a single-strand dinucleotide model using an empirical energy function. The low energy regions of the surface encompass known DNA forms and also identify previously unclassified conformers.