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Human α-defensin 5 (HD5) is one of cationic antimicrobial peptides which plays a crucial role in an innate immune system in human body. HD5 shows the killing activity against a broad spectrum of pathogenic bacteria by making a pore in a bacterial membrane and penetrating into a cytosol. Nonetheless, its pore-forming mechanisms remain unclear. Thus, in this work, the constant-velocity steered molecular dynamics (SMD) simulation was used to simulate the permeation of a dimeric HD5 into a gram-negative lipopolysaccharide (LPS) membrane model. Arginine-rich HD5 is found to strongly interact with a LPS surface. Upon arrival, arginines on HD5 interact with lipid A head groups (a top part of LPS) and then drag these charged moieties down into a hydrophobic core resulting in the formation of water-filled pore. Although all arginines are found to interact with a membrane, Arg13 and Arg32 appear to play a dominant role in the HD5 adsorption on a gram-negative membrane. Furthermore, one chain of a dimeric HD5 is required for HD5 adhesion. The interactions of arginine-lipid A head groups play a major role in adhering a cationic HD5 on a membrane surface and retarding a HD5 passage in the meantime. Graphical abstract

Cholesterol is an integral component of eukaryotic cell membranes and a key molecule in controlling membrane fluidity, organization, and other physicochemical parameters. It also plays a regulatory function in antibiotic drug resistance and the immune response of cells against viruses, by stabilizing the membrane against structural damage. While it iswell understood that, structurally, cholesterol exhibits a densification effect on fluid lipid membranes, its effects on membrane bending rigidity are assumed to be nonuniversal; i.e., cholesterol stiffens saturated lipid membranes, but has no stiffening effect on membranes populated by unsaturated lipids, such as 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). This observation presents a clear challenge to structure–property relationships and to our understanding of cholesterol-mediated biological functions. Here, using a comprehensive approach—combining neutron spin-echo (NSE) spectroscopy, solid-state deuterium NMR (²H NMR) spectroscopy, and molecular dynamics (MD) simulations—we report that cholesterol locally increases the bending rigidity of DOPC membranes, similar to saturated membranes, by increasing the bilayer’s packing density. All three techniques, inherently sensitive to mesoscale bending fluctuations, show up to a threefold increase in effective bending rigidity with increasing cholesterol content approaching a mole fraction of 50%. Our observations are in good agreement with the known effects of cholesterol on the area-compressibility modulus and membrane structure, reaffirming membrane structure–property relationships. The current findings point to a scale-dependent manifestation of membrane properties, highlighting the need to reassess cholesterol’s role in controlling membrane bending rigidity over mesoscopic length and time scales of important biological functions, such as viral budding and lipid–protein interactions.

Although the use of the tyrosine kinase inhibitors (TKIs) has been proved that it can save live in a cancer treatment, the currently used drugs bring in many undesirable side-effects. Therefore, the search for new drugs and an evaluation of their efficiency are intensively carried out. Recently, a series of eighteen imidazole[1,5-a]pyridine derivatives were synthetized by us, and preliminary analyses pointed out their potential to be an important platform for pharmaceutical development owing to their promising actions as anticancer agents and enzyme (kinase, HIV-protease,…) inhibitors. In the present theoretical study, we further analyzed their efficiency in using a realistic scenario of computational drug design. Our protocol has been developed to not only observe the atomistic interaction between the EGFR protein and our 18 novel compounds using both umbrella sampling and steered molecular dynamics simulations, but also determine their absolute binding free energies. Calculated properties of the 18 novel compounds were in detail compared with those of two known drugs, erlotinib and osimertinib, currently used in cancer treatment. Inspiringly the simulation results promote three imidazole[1,5-a]pyridine derivatives as promising inhibitors into a further step of clinical trials.

Background & objectives: The present study proposed a series of computational techniques such as homology modelling, molecular simulation, and molecular docking to be performed to explore the structural features and binding mechanism of Cytochrome c oxidase subunit I (COX1) protein with known inhibitors. Methods: Elucidation of the three-dimensional structure of COX1 protein was carried out by using MODELLER software. The modelled protein was validated using GROMACS, structural qualitative tools and web servers. Finally the model was docked with carbon monoxide (CO) and nitric oxide (NO) using Auto Dock Tools. Results: The three-dimensional structure of mitochondrial transmembrane protein COX1 was built using homology modelling based on high-resolution crystal structures of Bos taurus. Followed by inserting the lipid bilayer, molecular dynamics simulation was performed on the modelled protein structure. The modelled protein was validated using qualitative structural indices. Known inhibitors such as carbon monoxide (CO) and nitric oxide (NO) inhibit their active binding sites of mitochondrial COX1 and the inhibitors were docked into the active site of attained model. A structure-based virtual screening was performed on the basis of the active site inhibition with best scoring hits. The COX1 model was submitted and can be accessible from the Model Archive site through the following link https://www.modelarchive.org/doi/10.5452/ma-at44v. Interpretation & conclusion: Structural characterization and active site identification can be further used as target for the planning of potent mosquitocidal compounds, thereby assisting the information in the field of research.

Despite the biological importance of protein–protein complexes, determining their structures and association mechanisms remains an outstanding challenge. Here, we report the results of atomic-level simulations in which we observed five protein–protein pairs repeatedly associate to, and dissociate from, their experimentally determined native complexes using a molecular dynamics (MD)–based sampling approach that does not make use of any prior structural information about the complexes. To study association mechanisms, we performed additional, conventional MD simulations, in which we observed numerous spontaneous association events. A shared feature of native association for these five structurally and functionally diverse protein systems was that if the proteins made contact far from the native interface, the native state was reached by dissociation and eventual reassociation near the native interface, rather than by extensive interfacial exploration while the proteins remained in contact. At the transition state (the conformational ensemble from which association to the native complex and dissociation are equally likely), the protein–protein interfaces were still highly hydrated, and no more than 20% of native contacts had formed.

Orthologous proteins of species adapted to different temperatures exhibit differences in stability and function that are interpreted to reflect adaptive variation in structural “flexibility.” However, quantifying flexibility and comparing flexibility across proteins has remained a challenge. To address this issue, we examined temperature effects on cytosolic malate dehydrogenase (cMDH) orthologs from differently thermally adapted congeners of five genera of marine molluscs whose field body temperatures span a range of ∼60 °C. We describe consistent patterns of convergent evolution in adaptation of function [temperature effects on K M of cofactor (NADH)] and structural stability (rate of heat denaturation of activity). To determine how these differences depend on flexibilities of overall structure and of regions known to be important in binding and catalysis, we performed molecular dynamics simulation (MDS) analyses. MDS analyses revealed a significant negative correlation between adaptation temperature and heat-induced increase of backbone atom movements [root mean square deviation (rmsd) of main-chain atoms]. Root mean square fluctuations (RMSFs) of movement by individual amino acid residues varied across the sequence in a qualitatively similar pattern among orthologs. Regions of sequence involved in ligand binding and catalysis—termed mobile regions 1 and 2 (MR1 and MR2), respectively—showed the largest values for RMSF. Heat-induced changes in RMSF values across the sequence and, importantly, in MR1 and MR2 were greatest in cold-adapted species. MDS methods are shown to provide powerful tools for examining adaptation of enzymes by providing a quantitative index of protein flexibility and identifying sequence regions where adaptive change in flexibility occurs.

The PLUMED consortium unifies developers and contributors to PLUMED, an open-source library for enhanced-sampling, free-energy calculations and the analysis of molecular dynamics simulations. Here, we outline our efforts to promote transparency and reproducibility by disseminating protocols for enhanced-sampling molecular simulations.

Receptor–ligand interactions are essential for biological function and their binding strength is commonly explained in terms of static lock-and-key models based on molecular complementarity. However, detailed information on the full unbinding pathway is often lacking due, in part, to the static nature of atomic structures and ensemble averaging inherent to bulk biophysics approaches. Here we combine molecular dynamics and high-speed force spectroscopy on the streptavidin–biotin complex to determine the binding strength and unbinding pathways over the widest dynamic range. Experiment and simulation show excellent agreement at overlapping velocities and provided evidence of the unbinding mechanisms. During unbinding, biotin crosses multiple energy barriers and visits various intermediate states far from the binding pocket, while streptavidin undergoes transient induced fits, all varying with loading rate. This multistate process slows down the transition to the unbound state and favors rebinding, thus explaining the long lifetime of the complex. We provide an atomistic, dynamic picture of the unbinding process, replacing a simple two-state picture with one that involves many routes to the lock and ratedependent induced-fit motions for intermediates, which might be relevant for other receptor–ligand bonds.

Although various higher-order protein structure prediction methods have been developed, almost all of them were developed based on the three-dimensional (3D) structure information of known proteins. Here we predicted the short protein structures by molecular dynamics (MD) simulations in which only Newton’s equations of motion were used and 3D structural information of known proteins was not required. To evaluate the ability of MD simulationto predict protein structures, we calculated seven short test protein (10–46 residues) in the denatured state and compared their predicted and experimental structures. The predicted structure for Trp-cage (20 residues) was close to the experimental structure by 200-ns MD simulation. For proteins shorter or longer than Trp-cage, root-mean square deviation values were larger than those for Trp-cage. However, secondary structures could be reproduced by MD simulations for proteins with 10–34 residues. Simulations by replica exchange MD were performed, but the results were similar to those from normal MD simulations. These results suggest that normal MD simulations can roughly predict short protein structures and 200-ns simulations are frequently sufficient for estimating the secondary structures of protein (approximately 20 residues). Structural prediction method using only fundamental physical laws are useful for investigating non-natural proteins, such as primitive proteins and artificial proteins for peptide-based drug delivery systems.

NMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure of different states of the non-human NMDARs. Here we describe a model of a human NMDA receptor (hNMDAR) and its molecular dynamics (MD) before and after the binding of agonist ligands, glutamate and glycine. It is shown that the binding of ligands promotes a global reduction in molecular flexibility that produces a more tightly packed conformation than the unbound hNMDAR, and a higher cooperative regularity of moving. The ligand-induced synchronization of motion, identified on all structural levels of the modular hNMDA receptor is apparently a fundamental factor in channel gating. Although the time scale of the MD simulations (300 ns) was not sufficient to observe the complete gating event, the obtained data has shown the ligand-induced stabilization of hNMDAR that conforms the \"going to be open state\". We propose a mechanistic dynamic model of the ligand-dependent gating mechanism in the hNMDA receptor. At the binding of the ligands, the differently twisted conformations of the highly flexible receptor are stabilized in unique conformation with a linear molecular axis, which is a condition that is optimal for pore development. By searching the receptor surface, we have identified three new pockets, which are different from the pockets described in the literature as the potential and known positive allosteric modulator binding sites. A successful docking of two NMDAR modulators to their binding sites validates the model of a human NMDA receptor as a biological relevant target.