Docking Ligands on Protein Surfaces: The Case Study of Prion Protein.

Molecular docking of ligands targeting proteins undergoing fibrillization in neurodegenerative diseases is difficult because of the lack of deep binding sites. Here we extend standard docking methods with free energy simulations in explicit solvent to address this issue in the context of the prion protein surface. We focus on a specific ligand (2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide), which binds to the structured part of the protein as shown by NMR (Kuwata, K.

G protein inactive and active forms investigated by simulation methods.

Molecular dynamics and computational alanine scanning techniques have been used to investigate G proteins in their inactive state (the Galpha(i1)beta(1)gamma(2) heterotrimer) as well as in their empty and monomeric active states (Galpha(i1) subunit). We find that: (i) the residue Q204 of Galpha(i1) plays a key role for binding Gbeta(1)gamma(2) and is classified among the most relevant in the interaction with a key cellular partner, the so-called regulator of G protein signaling protein. The mutation of this residue to L, which is observed in a variety of diseases, provides still fair stability to the inactive state because of the formation of van der Waals interactions.

Deuterium isotope effects in A:T and A:U base pairs: a computational NMR study.

Recent measurements of trans-hydrogen bond deuterium isotope effects (DIEs) on 13C chemical shifts in nucleic acids (Vakonakis, I.; LiWang, A. C.

Structure and function of vanadium haloperoxidases.

A quantum mechanics/molecular mechanics study of the resting state of the vanadium dependent chloroperoxidase from fungi Curvularia inaequalis and of the early intermediates of the halide oxidation is reported. The investigation of different protonation states indicates that the enzyme likely consists of an anionic H2VO4- vanadate moiety where one hydroxo group is in axial position. The calculations suggest that the hydrogen peroxide binding may not involve an initial protonation of the vanadate cofactor.

Binding of phosphinate and phosphonate inhibitors to aspartic proteases: a first-principles study.

Phosphinate and phosphonate derivatives are potent inhibitors of aspartic proteases (APs). The affinity for the enzyme might be caused by the presence of low barrier hydrogen bonds between the ligand and the catalytic Asp dyad in the cleavage site. We have used density functional theory calculations along with hybrid quantum mechanics/molecular mechanics Car-Parrinello molecular dynamics simulations to investigate the hydrogen-bonding pattern at the binding site of the complexes of human immunodeficiency virus type-1 AP and the eukaryotic endothiapepsin and penicillopepsin.

Insights on HIV-1 Tat:P/CAF bromodomain molecular recognition from in vivo experiments and molecular dynamics simulations.

Structural and functional studies indicate that, through its bromodomain, the cellular acetyltransferase P/CAF binds the acetylated Tat protein of human immunodeficiency virus type 1 (HIV-1) and promotes transcriptional activation of the integrated provirus. Based on the NMR structure of P/CAF complexed with an acetylated Tat peptide, here we use molecular dynamics simulations to construct a model describing the interaction between full length Tat and the P/CAF bromodomain. Our calculations show that the protein-protein interface involves hydrophobic interactions between the P/CAF ZA loop and the Tat core domain.

Physics of solid and liquid alkali halide surfaces near the melting point.

This paper presents a broad theoretical and simulation study of the high-temperature behavior of crystalline alkali halide surfaces typified by NaCl(100), of the liquid NaCl surface near freezing, and of the very unusual partial wetting of the solid surface by the melt. Simulations are conducted using two-body rigid-ion Born-Mayer-Huggins-Fumi-Tosi (BMHFT) potentials, with full treatment of long-range Coulomb forces. After a preliminary check of the description of bulk NaCl provided by these potentials, which seems generally good even at the melting point, we carry out a new investigation of solid and liquid surfaces.

Unwinding the helical linker of calcium-loaded calmodulin: a molecular dynamics study.

The fold of calmodulin (CaM) consists of two globular domains connected by a helical segment (the linker), whose conformational properties play a crucial role for the protein's molecular recognition processes. Here we investigate the structural properties of the linker by performing a 11.5 ns molecular dynamics (MD) simulation of calcium-loaded human CaM in aqueous solution.

A homology model of the pore region of HCN channels.

HCN channels are activated by membrane hyperpolarization and regulated by cyclic nucleotides, such as cyclic adenosine-mono-phosphate (cAMP). Here we present structural models of the pore region of these channels obtained by using homology modeling and validated against spatial constraints derived from electrophysiological experiments. For the construction of the models we make two major assumptions, justified by electrophysiological observations: i), in the closed state, the topology of the inner pore of HCN channels is similar to that of K(+) channels.

Molecular basis of the allosteric mechanism of cAMP in the regulatory PKA subunit.

The second messenger cyclic Adenosine MonoPosphate (cAMP) mediates many biological process by interacting with structurally conserved nucleotide binding domains (cNBD's). Here, we use molecular dynamics simulations on RIIbeta-PKA, one of the best characterized members of the cNBD family, in presence and absence of cAMP. The results of our calculations are fully consistent with the available experimental data and suggest that the key factor of the cAMP allosteric mechanism in cNBDS's is the increased flexibility of the protein upon ligand release along with a mechanical coupling between helical segments.

Evolutionarily conserved functional mechanics across pepsin-like and retroviral aspartic proteases.

The biological function of the aspartic protease from HIV-1 has recently been related to the conformational flexibility of its structural scaffold. Here, we use a multistep strategy to investigate whether the same mechanism affects the functionality in the pepsin-like fold. (i) We identify the set of conserved residues by using sequence-alignment techniques.

Comparative analysis of HIV-1 Tat variants.

HIV-1 Tat protein is a crucial element for viral replication; therefore, its inhibition might be exploited against the AIDS infection. To gain insights on the natural variability of this protein, we present a comparative investigation on the relationship between the primary sequences and the experimentally available three-dimensional structures from the HIV-1 Tat variants Z2, BRU, and MAL. Our computational tools include sequence conservation algorithms, structural analysis, electrostatic modeling, and molecular dynamics (MD) simulations.

A proficient enzyme: insights on the mechanism of orotidine monophosphate decarboxylase from computer simulations.

Decarboxylation of orotidine 5'-monophosphate (Omp) to uridine 5'-monophosphate by orotidine 5'-monophosphate decarboxylase (ODCase) is currently the object of vivid debate. Here, we clarify its enzymatic activity with long time scale classical molecular dynamics and hybrid ab initio Car-Parrinello/molecular mechanics simulations. The lack of structural (experimental) information on the ground state of ODCase/Omp complex is overcome by a careful construction of the model and the analysis of three different strains of the enzyme.

On the quantum nature of an excess proton in liquid hydrogen fluoride.

Liquid hydrogen fluoride consists of chains of hydrogen-bonded molecules. The nature of an excess proton in liquid HF, which is of interest not only for its own sake, but also in relation to super-acid chemistry and to its behavior in water, has been studied using computer simulations. The methodology employed is the density-functional-theory-based path-integral Car-Parrinello ab initio molecular dynamics.

Dynamics and energetics of water permeation through the aquaporin channel.

Structural properties of water inside bovine aquaporin-1 are investigated by molecular simulation. The calculations, which are based on the recently determined X-ray structure at 2.2 A resolution (Sui et al.

Protonation state of Asp120 in the binuclear active site of the metallo-beta-lactamase from Bacteroides fragilis.

The determination of the protonation state of enzyme active sites may be crucial for the investigation of their mechanism of action. In the bizinc beta-lactamase family of enzymes, no consensus has been reached on the protonation state of a fully conserved amino acid present in the active site, Asp120. To address this issue, we carry out here density functional theory (DFT) calculations on large models (based on Bacteroides fragilis X-ray structure) which include the metal coordination polyhedron and groups interacting with it.