The associative memory, water mediated, structure and energy model (AWSEM) is a coarse-grained protein force field. AWSEM contains physically motivated terms, such as hydrogen bonding, well bioinformatically based local biasing term, which efficiently takes into account many-body effects that are modulated by the sequence. When combined with appropriate or global alignments to choose memories, can be used perform de novo prediction. Herein we present prediction results for particular choice...

The protein frustratometer is an energy landscape theory-inspired algorithm that aims at localizing and quantifying the energetic frustration present in molecules. Frustration a useful concept for analyzing proteins' biological behavior. It compares distributions of native state with respect to structural decoys. network minimally frustrated interactions encompasses folding core molecule. Sites high local often correlate functional regions such as binding sites involved allosteric...

Significance Natural protein sequences, being the result of random mutation coupled with natural selection, have remarkable properties that are not typical unselected including ability to robustly fold an organized structure is needed function. We estimate selection temperature, effective temperature at which sequences were selected by evolution, for eight families and compare these values experimental data folding temperatures proteins in each family. The measures importance maintaining...

We investigate protein–protein association using the associative-memory, water-mediated, structure, and energy model (AWSEM), a coarse-grained protein folding that has been optimized energy-landscape theory. The potential was originally parameterized by enforcing funneled nature for database of dimeric interfaces but later further to create landscapes individual monomeric proteins. ability predict not tested previously. present results show simulated annealing indeed is able successfully...

While being long in range and therefore weakly specific, electrostatic interactions are able to modulate the stability folding landscapes of some proteins. The relevance forces for steering docking proteins each other is widely acknowledged, however, role electrostatics establishing specifically funneled their protein structure prediction still not clear. By introducing Debye-Hückel potentials that mimic long-range into Associative memory, Water mediated, Structure, Energy Model (AWSEM), a...

Frustration from strong interdomain interactions can make misfolding a more severe problem in multidomain proteins than single-domain proteins. On the basis of bioinformatic surveys, it has been suggested that lowering sequence identity between neighboring domains is one nature’s solutions to problem. We investigate folding using associative-memory, water-mediated, structure and energy model (AWSEM), predictive coarse-grained protein force field. find reducing not only decreases formation...

Abstract To function, biomolecules require sufficient specificity of interaction as well stability to live in the cell while still being able move. Thermodynamic only a limited number specific structures is important so prevent promiscuous interactions. The individual interactions proteins, therefore, have evolved collectively give funneled minimally frustrated landscapes but some strategic parts biomolecular sequences located at sites structure been selected be order allow both motion and...

We present OpenAWSEM and Open3SPN2, new cross-compatible implementations of coarse-grained models for protein (AWSEM) DNA (3SPN2) molecular dynamics simulations within the OpenMM framework. These retain chemical accuracy intrinsic efficiency original while adding GPU acceleration ease forcefield modification provided by OpenMM’s Custom Forces software By utilizing GPUs, we achieve around a 30-fold speedup in protein-DNA over existing LAMMPS-based running on single CPU core. showcase benefits...

Liquid–liquid phase separation (LLPS) of heterogeneous ribonucleoproteins (hnRNPs) drives the formation membraneless organelles, but structural information about their assembled states is still lacking. Here, we address this challenge through a combination protein engineering, native ion mobility mass spectrometry, and molecular dynamics simulations. We used an LLPS-compatible spider silk domain pH changes to control self-assembly hnRNPs FUS, TDP-43, hCPEB3, which are implicated in...

Abstract This review is a tutorial for scientists interested in the problem of protein structure prediction, particularly those using coarse‐grained molecular dynamics models which are optimized lessons learned from energy landscape theory folding. We also present results AMH/AMC/AMW/AWSEM family folding to illustrate points covered first part article. Accurate prediction can be used investigate wide range conceptual and mechanistic issues outside prediction; specifically, paper concludes by...

Significance How a protein folds in membrane is problem of central biological significance. Although extensively investigated for globular proteins, there are very limited data available proteins due to the difficulties finding tractable model system. We present study folding six-transmembrane helix protein, rhomboid protease GlpG, which according two-state membrane-mimicking mixed micelle surfactant By recording kinetics and unfolding 69 GlpG mutants performing an extensive ϕ-value...

Filaments made up of different isoforms tau protein are associated with a variety neurodegenerative diseases. the 4R-tau isoform, which has four repeat regions (R1 to R4), found in patients suffering from Alzheimer's disease, while filaments 3R-tau contains only three units (R1, R3, and Pick's disease (frontotemporal dementia). In this work, predictive coarse-grained force field, associative memory water-mediated structure energy model (AWSEM), is used study landscapes nucleation two fibrils...

Significance The structural dynamics of the dendritic synapse, arising from remodeling actin cytoskeletons, has been widely associated with memory and cognition. is regulated by intracellular Ca 2+ levels. Under low concentration, filaments are bundled a calcium signaling protein, CaMKII. When concentration raised, CaMKII dissociates opens window for remodeling. At present, molecular details bundling regulation elusive. Herein we use experimental tools along simulations to construct model...

Significance This study leverages a predictive protein-folding simulation model to the free energy landscapes of fused oligomeric constructs quantify conditions under which these spontaneously misfold. Constructs this type have been used probe early stages aggregation in laboratory. Oligomeric species may be toxic agents misfolding-related diseases. The critical structures that initiate are shown depend on specific sequence signals and thermodynamic conditions. Our results also suggest...

We explore the hypothesis that folding landscapes of membrane proteins are funneled once proteins' topology within is established. extend a protein model, associative memory, water-mediated, structure, and energy model (AWSEM) by adding an implicit potential reoptimizing force field to account for differing nature interactions stabilize lipid membranes, yielding we call AWSEM-membrane. Once set in membrane, hydrophobic attractions play lesser role finding native whereas polar-polar more...

Actomyosin networks give cells the ability to move and divide. These contract expand while being driven by active energy-consuming processes such as motor protein walking actin polymerization. Actin dynamics is also regulated actin-binding proteins, actin-related 2/3 (Arp2/3) complex. This complex generates branched filaments, thereby changing overall organization of network. In this work, spatiotemporal patterns dynamical assembly accompanying branching-induced reorganization caused Arp2/3...

We explore the similarities and differences between energy landscapes of proteins that have been selected by nature those some designed humans. Natural evolved to function as well fold, this is a source energetic frustration. The sequence Top7, on other hand, was with architecture alone in mind using only native state stability optimization criterion. Its topology had not previously observed nature. Experimental studies show folding kinetics Top7 more complex than otherwise comparable...

The temperature-pressure behavior of two proteins, ubiquitin and λ-repressor, is explored using a realistically coarse-grained physicochemical model, the associative memory, water mediated, structure energy model (AWSEM). phase diagram across plane obtained by perturbing mediated interactions in Hamiltonian systematically. diagrams calculated with direct simulations along an extended bridge sampling estimator show main features found experimentally, including both cold-...

Abstract Protein sequences have evolved to fold into functional structures, resulting in families of diverse protein that all share the same overall fold. One can harness family sequence data infer likely contacts between pairs residues. In current study, we combine this kind inference from coevolutionary information with a coarse‐grained force field ordinarily used single input, Associative memory, Water mediated, Structure and Energy Model (AWSEM), achieve improved structure prediction....

Membrane protein folding mechanisms and rates are notoriously hard to determine. A recent force spectroscopy study of the an α-helical membrane protein, GlpG, showed that folded state has a very high kinetic stability relatively low thermodynamic stability. Here, we simulate spontaneous insertion GlpG into bilayer. An energy landscape analysis simulations suggests folds via sequential helical hairpins. The rate-limiting step involves simultaneous final hairpin. striking features GlpG's...

Many unrelated proteins and peptides have been found spontaneously to form amyloid fibers above a critical concentration. Even for single sequence, however, the fold is not well-defined structure. Although cross-β hydrogen bonding pattern common all amyloids, other aspects of fiber structures are sensitive both sequence aggregating solvent conditions under which aggregation occurs. Amyloid easy identify grossly characterize using microscopy, but their insolubility aperiodicity along...