Abstract Summary: Wordom is a versatile program for manipulation of molecular dynamics trajectories and efficient analysis simulations. Original tools in include procedure to evaluate significance sampling principal component as well modules clustering multiple conformations evaluation order parameters folding aggregation. The was developed with special emphasis on user-friendliness, effortless addition new handling large sets trajectories. Availability: distributed full source code (in the...

The p53 cancer mutation Y220C induces formation of a cavity on the protein's surface that can accommodate stabilizing small molecules. We combined fragment screening and molecular dynamics to assess druggability p53-Y220C map ligand interaction sites within mutational cavity. Elucidation binding mode hits by crystallography yielded clear picture how drug might dock in Simulations solvate protein with isopropanol found additional extend druggable surface. Moreover, structural observations...

The tumor suppressor p53 is a member of the emerging class proteins that have both folded and intrinsically disordered domains, which are challenge to structural biology. Its N-terminal domain (NTD) linked core domain, has link tetramerization followed by C-terminal domain. quaternary structure human been solved combination NMR spectroscopy, electron microscopy, small-angle X-ray scattering (SAXS), NTD ensemble SAXS. murine reported different structure, with N C termini interacting. Here, we...

The affinity of protein surface amino acids for poly(ethylene glycol) is used to build a quantitative model adsorption on PEGylated nanoparticles.

We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of mutome, we now analyzed effects other cancer-associated mutations at codon 220 on structure, stability, and dynamics DNA-binding domain (DBD). found oncogenic Y220H, Y220N, Y220S are also highly destabilizing, suggesting they largely unfolded under physiological conditions. A high-resolution crystal...

The data collected along a metadynamics simulation can be used to recover information about the underlying unbiased system by means of reweighting procedure. Here, we analyze behavior several techniques in terms quality reconstruction free energy landscape early stages and propose simple scheme that relate other techniques. We then show reconstructed from reweighted more accurate than negative bias potential depending on technique, stage simulation, adoption well-tempered or standard...

Fibrinogen is a serum multi-chain protein which, when activated, aggregates to form fibrin, one of the main components blood clot. Fibrinolysis controls clot dissolution through action enzyme plasmin, which cleaves fibrin at specific locations. Although biochemical factors involved in formation and lysis have been identified, clear mechanistic picture how these processes take place not available yet. This would be instrumental, for example, design improved thrombolytic or anti-haemorrhagic...

Nanoparticles coated with hydrophilic polymers often show a reduction in unspecific interactions the biological environment, which improves their biocompatibility. The molecular determinants of this are not very well understood yet, and knowledge may help improving nanoparticle design. Here we address, using dynamics simulations, human serum albumin, most abundant protein, two promising used for coating therapeutic nanoparticles, poly(ethylene-glycol) poly-sarcosine. By simulating protein...

In Phi-value analysis, the effects of mutations on folding kinetics are compared with corresponding thermodynamic stability to investigate structure protein-folding transition state (TS). Here, molecular dynamics (MD) simulations (totaling 0.65 ms) have been performed for a large set single-point mutants 20-residue three-stranded antiparallel beta-sheet peptide. Between 57 and 120 events were sampled at near equilibrium each mutant, allowing accurate estimates folding/unfolding rates...

Fibrinogen, a blood glycoprotein of vertebrates, plays an essential role in clotting by polymerizing into fibrin when activated. Upon adsorption on material surfaces, it also contributes to determine their biocompatibility and has been implicated the onset thrombosis inflammation at medical implants. Here we present first fully atomistic simulations initial stages process fibrinogen mica graphite surfaces. The reveal weak that allows frequent desorption reorientation events. This is driven...

We report high temperature molecular dynamics simulations of the unfolding TRPZ1 peptide using an explicit model for solvent. The system has been simulated a total 6 mus with 100-ns minimal continuous stretches trajectory. populated states along are identified by monitoring multiple observables, probing both structure and flexibility conformations. Several refolding transition pathways sampled analyzed. process occurs in two steps because accumulation metastable on-pathway intermediate state...

The cavity-creating p53 cancer mutation Y220C is an ideal paradigm for developing small-molecule drugs based on protein stabilization. Here, we have systematically analyzed the structural and stability effects of all oncogenic Tyr-to-Cys mutations (Y126C, Y163C, Y205C, Y220C, Y234C, Y236C) in DNA-binding domain (DBD). They were highly destabilizing, drastically lowering melting temperature by 8-17 °C. In contrast, two non-cancerous mutations, Y103C Y107C, had only a moderate effect...

Lipid-based nanomaterials are used as a common delivery vehicle for RNA therapeutics. They typically include formulation containing ionizable cationic lipids, cholesterol, phospholipids, and small molar fraction of PEGylated lipids. The lipids considered crucial element the way they mediate interactions with anionic function pH. Here, we show, by means molecular dynamics simulation lipid formulations two different (DLinDMA DLinDAP), that direct those RNA, taken alone, may not be sufficient...

Lipid-based nanoparticles and lipoplexes containing ionizable lipids are among the most successful nanocarriers for mRNA-based therapies. The molecular structure of these assemblies is still not fully understood, as well role played by lipids. SAXS experiments have shown that including lipid 2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), under specific conditions, a lamellar structure, where bilayers separated mRNA-rich layers, with an overall spacing between 6.5 8.0 nm complex...

The assumption that similar structures have folding probabilities ($p_{fold}$) leads naturally to a procedure evaluate $p_{fold}$ for every snapshot saved along an equilibrium folding-unfolding trajectory of structured peptide or protein. utilizes structurally homogeneous clustering and does not require any additional simulation. It can be used detect multiple pathways as shown three-stranded antiparallel $β$-sheet investigated by implicit solvent molecular dynamics simulations.

Poly(ethylene-glycol) (PEG) is a polymer used to coat therapeutic preparations, like drugs or drug nanocarriers, and improve their efficacy. This effect probably due reduction of the interactions coated species with host organism. Nevertheless, experiments show that PEGylated materials do interact surrounding biological milieu, in particular blood proteins. Here, we use atomistic molecular dynamics simulations characterize between several In these simulations, proteins are immersed mixture...

We discuss methods for the determination of effective pairwise interactions between amino acids in globular proteins order to be able easily recognize native state conformation any protein sequence among a set decoy structures. The first method entails application numerical strategy training that maximizes fold stability with respect alternative extracted parameters are shown very reliable identifying states (unrelated those set) thousands conformations. Folding transition temperatures...