Machine learning can be used to distinguish protein families and generate new proteins belonging to those families.

Proteins are classified into families based on evolutionary relationships and common structure-function characteristics. Availability of large data sets of gene-derived protein sequences drives this classification. Sequence space is exponentially large, making it difficult to characterize family differences.

Conformational Ensembles Exhibit Extensive Molecular Recognition Features.

Intrinsically disordered proteins (IDPs) are important for signaling and regulatory pathways. In contrast to folded proteins, they sample a diverse conformational space. IDPs have residue ranges within a sequence that have been referred to as molecular recognition features (MoRFs).

Reweighting ensemble probabilities with experimental histogram data constraints using a maximum entropy principle.

Entropy maximization methods that update a probability distribution () to a new distribution () with the use of externally known, averaged constraints find use in diverse areas. Jaynes developed a Maximum Entropy Procedure (MEP) that is an objective approach to incorporate external data to update () to (). In this work, we consider the MEP in the context of external data known from a probability distribution versus that from a mean and a few higher moments.

Generating Intrinsically Disordered Protein Conformational Ensembles from a Database of Ramachandran Space Pair Residue Probabilities Using a Markov Chain.

Intrinsically disordered proteins (IDPs), involved in regulatory pathways and cell signaling, sample a range of conformations. Constructing structural ensembles of IDPs is a difficult task for both experiment and simulation. In this work, we produce potential IDP ensembles using an existing database of pair residue φ and ψ angle probabilities chosen from turn, coil, and bend parts of sequences from the Protein Data Bank.

Generating intrinsically disordered protein conformational ensembles from a Markov chain.

Intrinsically disordered proteins (IDPs) sample a diverse conformational space. They are important to signaling and regulatory pathways in cells. An entropy penalty must be payed when an IDP becomes ordered upon interaction with another protein or a ligand.

Molecular Dynamics of Oxazole Yellow Dye in its Ground and First Excited Electronic States in Solution and when Intercalated in dsDNA.

Oxazole yellow (YOPRO), a cyanine dye consisting of benzoxazole and quinoline rings connected by a linker, is almost nonfluorescent in water, but its fluorescence is greatly enhanced after intercalation in double-stranded DNA, forming the basis of DNA concentration assays. To explore this difference, new potential energy surfaces for the two linker dihedral angles in the ground S0 and first excited S1 electronic states are developed. Umbrella sampling molecular dynamics is used to obtain the free energy of rotation around the two dihedral angles of the linker.

Hinge action versus grip in translocation by RNA polymerase.

Based on molecular dynamics simulations and functional studies, a conformational mechanism is posited for forward translocation by RNA polymerase (RNAP). In a simulation of a ternary elongation complex, the clamp and downstream cleft were observed to close. Hinges within the bridge helix and trigger loop supported generation of translocation force against the RNA-DNA hybrid resulting in opening of the furthest upstream i-8 RNA-DNA bp, establishing conditions for RNAP sliding.

Glucose-Promoted Localization Dynamics of Excess Electrons in Aqueous Glucose Solution Revealed by Ab Initio Molecular Dynamics Simulation.

Ab initio molecular dynamics simulations reveal that an excess electron (EE) can be more efficiently localized as a cavity-shaped state in aqueous glucose solution (AGS) than in water. Compared with that (∼1.5 ps) in water, the localization time is shortened by ∼0.

Conformational transition in signal transduction: metastable states and transition pathways in the activation of a signaling protein.

Signal transduction is of vital importance to the growth and adaptation of living organisms. The key to understand mechanisms of biological signal transduction is elucidation of the conformational dynamics of its signaling proteins, as the activation of a signaling protein is fundamentally a process of conformational transition from an inactive to an active state. A predominant form of signal transduction for bacterial sensing of environmental changes in the wild or inside their hosts is a variety of two-component systems, in which the conformational transition of a response regulator (RR) from an inactive to an active state initiates responses to the environmental changes.

Dihedral angle entropy measures for intrinsically disordered proteins.

Protein stability is based on a delicate balance between energetic and entropic factors. Intrinsically disordered proteins (IDPs) interacting with a folded partner protein in the act of binding can order the IDP to form the correct functional interface by decrease in the overall free energy. In this work, we evaluate the part of the entropic cost of ordering an IDP arising from their dihedral states.

Five checkpoints maintaining the fidelity of transcription by RNA polymerases in structural and energetic details.

Transcriptional fidelity, which prevents the misincorporation of incorrect nucleoside monophosphates in RNA, is essential for life. Results from molecular dynamics (MD) simulations of eukaryotic RNA polymerase (RNAP) II and bacterial RNAP with experimental data suggest that fidelity may involve as many as five checkpoints. Using MD simulations, the effects of different active site NTPs in both open and closed trigger loop (TL) structures of RNAPs are compared.

Simulations of potentials of mean force for separating a leucine zipper dimer and the basic region of a basic region leucine zipper dimer.

Basic region leucine zipper (bZIP) transcription factors involved in DNA recognition are dimeric proteins. The monomers consist of two subdomains, a leucine zipper sequence responsible for dimerization and a highly basic DNA recognition sequence. Leucine zippers are strongly dimerized, and in a bZIP, the basic region can, in the absence of DNA, undergo extensive relative monomer-to-monomer fluctuations.

Conformational transition of response regulator RR468 in a two-component system signal transduction process.

Signal transduction can be accomplished via a two-component system (TCS) consisting of a histidine kinase (HK) and a response regulator (RR). In this work, we simulate the response regulator RR468 from Thermotoga maritima, in which phosphorylation and dephosphorylation of a conserved aspartate residue acts as a switch via a large conformational change concentrated in three proximal loops. A detailed view of the conformational transition is obscured by the lack of stability of the intermediate states, which are difficult to detect using common structural biology techniques.

Transition paths of Met-enkephalin from Markov state modeling of a molecular dynamics trajectory.

Conformational states and their interconversion pathways of the zwitterionic form of the pentapeptide Met-enkephalin (MetEnk) are identified. An explicit solvent molecular dynamics (MD) trajectory is used to construct a Markov state model (MSM) based on dihedral space clustering of the trajectory, and transition path theory (TPT) is applied to identify pathways between open and closed conformers. In the MD trajectory, only four of the eight backbone dihedrals exhibit bistable behavior.

Bending Vibration-Governed Solvation Dynamics of an Excess Electron in Liquid Acetonitrile Revealed by Ab Initio Molecular Dynamics Simulation.

We report an ab initio molecular dynamics simulation study of the solvation and dynamics of an excess electron in liquid acetonitrile (ACN). Four families of states are observed: a diffusely solvated state and three ACN core-localized states with monomer core, quasi-dimer (π*-Rydberg mode) core, and dual-core/dimer core (a coupled dual-core). These core localized states cannot be simply described as the corresponding anions because only a part of the excess electron resides in the core molecule(s).

Variance of a potential of mean force obtained using the weighted histogram analysis method.

A potential of mean force (PMF) that provides the free energy of a thermally driven system along some chosen reaction coordinate (RC) is a useful descriptor of systems characterized by complex, high dimensional potential energy surfaces. Umbrella sampling window simulations use potential energy restraints to provide more uniform sampling along a RC so that potential energy barriers that would otherwise make equilibrium sampling computationally difficult can be overcome. Combining the results from the different biased window trajectories can be accomplished using the Weighted Histogram Analysis Method (WHAM).

Excess dielectron in an ionic liquid as a dynamic bipolaron.

We report an ab initio molecular dynamics simulation study on the accommodation of a dielectron in a pyridinium ionic liquid in both the singlet and triplet state. In contrast to water and liquid ammonia, a dielectron does not prefer to reside in cavity-shaped structures in the ionic liquid. Instead, it prefers to be distributed over more cations, with long-lived diffuse and short-lived localized distributions, and with a triplet ground state and a low-lying, open-shell singlet excited state.

The RNA polymerase bridge helix YFI motif in catalysis, fidelity and translocation.

The bridge α-helix in the β' subunit of RNA polymerase (RNAP) borders the active site and may have roles in catalysis and translocation. In Escherichia coli RNAP, a bulky hydrophobic segment near the N-terminal end of the bridge helix is identified (β' 772-YFI-774; the YFI motif). YFI is located at a distance from the active center and adjacent to a glycine hinge (β' 778-GARKG-782) involved in dynamic bending of the bridge helix.

Solvation and evolution dynamics of an excess electron in supercritical CO2.

We present an ab initio molecular dynamics simulation of the dynamics of an excess electron solvated in supercritical CO2. The excess electron can exist in three types of states: CO2-core localized, dual-core localized, and diffuse states. All these states undergo continuous state conversions via a combination of long lasting breathing oscillations and core switching, as also characterized by highly cooperative oscillations of the excess electron volume and vertical detachment energy.

Molecular dynamics and mutational analysis of the catalytic and translocation cycle of RNA polymerase.

Background: During elongation, multi-subunit RNA polymerases (RNAPs) cycle between phosphodiester bond formation and nucleic acid translocation. In the conformation associated with catalysis, the mobile "trigger loop" of the catalytic subunit closes on the nucleoside triphosphate (NTP) substrate. Closing of the trigger loop is expected to exclude water from the active site, and dehydration may contribute to catalysis and fidelity.

Simulations of temperature and salt concentration effects on bZIP, a basic region leucine zipper.

Basic region leucine zipper (bZIP) transcription factors are dimeric proteins that recognize DNA. The monomers consist of a leucine zipper subdomain responsible for dimerization and a highly basic DNA recognition subdomain. Twelve explicit solvent molecular dynamics (MD) trajectories were run on the GCN4 bZIP transcriptional factor in the absence of DNA at three temperatures and two ion concentrations (0 mM with Cl(-) ions to neutralize the bZIP and 200 mM with additional Na(+) and Cl(-) ions) to probe the conformational ensemble that the basic region samples.

Ferreting out correlations from trajectory data.

Thermally driven materials characterized by complex energy landscapes, such as proteins, exhibit motions on a broad range of space and time scales. Principal component analysis (PCA) is often used to extract modes of motion from protein trajectory data that correspond to coherent, functional motions. In this work, two other methods, maximum covariance analysis (MCA) and canonical correlation analysis (CCA) are formulated in a way appropriate to analyze protein trajectory data.

A hamiltonian replica exchange method for building protein-protein interfaces applied to a leucine zipper.

Leucine zippers consist of alpha helical monomers dimerized (or oligomerized) into alpha superhelical structures known as coiled coils. Forming the correct interface of a dimer from its monomers requires an exploration of configuration space focused on the side chains of one monomer that must interdigitate with sites on the other monomer. The aim of this work is to generate good interfaces in short simulations starting from separated monomers.

How many atoms are required to characterize accurately trajectory fluctuations of a protein?

Large molecules, whose thermal fluctuations sample a complex energy landscape, exhibit motions on an extended range of space and time scales. Principal component analysis (PCA) is often used to extract dominant motions that in proteins are typically domain motions. These motions are captured in the large eigenvalue (leading) principal components.