arXiv subjects

Marek Cieplak

Publications and source records attributed to Marek Cieplak.

At least 19 recordsLinked to original sources

arXiv2024

Contact-based molecular dynamics of structured and disordered proteins in a coarse-grained model: fixed contacts, switchable contacts and those described by pseudo-improper-dihedral angles

We present a coarse-grained C$α$-based protein model that can be used to simulate structured, intrinsically disordered and partially disordered proteins. We use a Go-like potential for the structured parts and two different variants of a transferable potential for the disordered parts. The first variant uses dynamic structure-based (DSB) contacts that form and disappear quasi-adiabatically during the simulation. By using specific structural criteria we distinguish sidechain-sidechain, sidechain-backbone and backbone-backbone contacts. The second variant is a non-radial multi-body pseudo-improper-dihedral (PID) potential that does not include time-dependent terms but requires more computational resources. Our model can simulate in reasonable time thousands of residues on millisecond time scales.

cond-mat.soft↗

arXiv2021

Conformational Biases of α-Synuclein and Formation of Transient Knots

We study local conformational biases in the dynamics of α-synuclein by using all-atom simulations with explicit and implicit solvents. The biases are related to the frequency of the specific contact formation. In both approaches, the protein is intrinsically disordered, and its strongest bias is to make bend and turn local structures. The explicit-solvent conformations can be substantially more extended which allows for formation of transient trefoil knots, both deep and shallow, that may last for up to 5 μs. The two-chain self-association events, both short- and long-lived, are dominated by formation of contacts in the central part of the sequence. This part tends to form helices when bound to a micelle.

q-bio.BM↗

arXiv2018

Self-assembly of model proteins into virus capsids

We consider self-assembly of proteins into a virus capsid by the methods of molecular dynamics. The capsid corresponds either to SPMV or CCMV and is studied with and without the RNA molecule inside. The proteins are flexible and described by the structure-based coarse-grained model augmented by electrostatic interactions. Previous studies of the capsid self-assembly involved solid objects of a supramolecular scale, e.g. corresponding to capsomeres, with engineered couplings and stochastic movements. In our approach, a single capsid is dissociated by an application of a high temperature for a variable period and then the system is cooled down to allow for self-assembly. The restoration of the capsid proceeds to various extent, depending on the nature of the dissociated state, but is rarely complete because some proteins depart too far unless the process takes place in a confined space.

q-bio.BM↗

arXiv2018

Disordered peptide chains in an α-C-based coarse-grained model

We construct a one-bead-per-residue coarse-grained dynamical model to describe intrinsically disordered proteins at significantly longer timescales than in the all-atom models. In this model, inter-residue contacts form and disappear during the course of the time evolution. The contacts may arise between the sidechains, the backbones or the sidechains and backbones of the interacting residues. The model yields results that are consistent with many all-atom and experimental data on these systems. We demonstrate that the geometrical properties of various homopeptides differ substantially in this model. In particular, the average radius of gyration scales with the sequence length in a residue-dependent manner.

q-bio.BM↗

arXiv2018

Proteins at air-water and oil-water interfaces in an all-atom model

We study the behavior of five proteins at the air-water and oil-water interfaces by all-atom molecular dynamics. The proteins are found to get distorted when pinned to the interface. This behavior is consistent with the phenomenological way of introducing the interfaces in a coarse-grained model through a force that depends on the hydropathy indices of the residues. Proteins couple to the oil-water interface stronger than to the air- water one. They diffuse slower at the oil-water interface but do not depin from it, whereas depinning events are observed at the other interface. The reduction of the disulfide bonds slows the diffusion down.

q-bio.BM↗

arXiv2017

Structural entanglements in protein complexes

We consider multi-chain protein native structures and propose a criterion that determines whether two chains in the system are entangled or not. The criterion is based on the behavior observed by pulling at both temini of each chain simultaneously in the two chains. We have identified about 900 entangled systems in the Protein Data Bank and provided a more detailed analysis for several of them. We argue that entanglement enhances the thermodynamic stability of the system but it may have other functions: burying the hydrophobic residues at the interface, and increasing the DNA or RNA binding area. We also study the folding and stretching properties of the knotted dimeric proteins MJ0366, YibK and bacteriophytochrome. These proteins have been studied theoretically in their monomeric versions so far. The dimers are seen to separate on stretching through the tensile mechanism and the characteristic unraveling force depends on the pulling direction.

q-bio.BM↗

arXiv2017

Structural changes in barley protein LTP1 isoforms at air-water interfaces

We use a coarse-grained model to study the conformational changes in two barley proteins, LTP1 and its ligand adduct isoform LTP1b, that result from their adsorption to the air-water interface. The model introduces the interface through hydropathy indices. We justify the model by all-atom simulations. The choice of the proteins is motivated by making attempts to understand formation and stability of foam in beer. We demonstrate that both proteins flatten out at the interface and can make a continuous stabilizing and denser film. We show that the degree of the flattening depends on the protein -- the layers of LTP1b should be denser than those of LTP1 -- and on the presence of glycation. It also depends on the number ($\le 4$) of the disulfide bonds in the proteins. The geometry of the proteins is sensitive to the specificity of the absent bonds. We provide estimates of the volume of cavities of the proteins when away from the interface.

q-bio.BM↗

arXiv2017

Topological transformations in proteins: effects of heating and proximity of an interface

Using a structure-based coarse-grained model of proteins, we study the mechanism of unfolding of knotted proteins through heating. We find that the dominant mechanisms of unfolding depend on the temperature applied and are generally distinct from those identified for folding at its optimal temperature. In particular, for shallowly knotted proteins, folding usually involves formation of two loops whereas unfolding through high-temperature heating is dominated by untying of single loops. Untying the knots is found to generally precede unfolding unless the protein is deeply knotted and the heating temperature exceeds a threshold value. We then use a phenomenological model of the air-water interface to show that such an interface can untie shallow knots, but it can also make knots in proteins that are natively unknotted.

q-bio.BM↗

arXiv2016

Unfolding knots by proteasome-like systems: simulations of the behaviour of folded and neurotoxic proteins

Knots in proteins have been proposed to resist proteasomal degradation. Ample evidence associates proteasomal degradation with neurodegeneration. One interesting possibility is that indeed knotted conformers stall this machinery leading to toxicity. However, although the proteasome is known to unfold mechanically its substrates, at present there are no experimental methods to emulate this particular traction geometry. Here, we consider several dynamical models of the proteasome in which the complex is represented by an effective potential with an added pulling force. This force is meant to induce translocation of a protein or a polypeptide into the catalytic chamber. The force is either constant or applied periodically. The translocated proteins are modelled in a coarse-grained fashion. We do comparative analysis of several knotted globular proteins and the transiently knotted polyglutamine tracts of length 60 alone and fused in exon 1 of the huntingtin protein. Huntingtin is associated with Huntington disease, a well-known genetically-determined neurodegenerative disease. We show that the presence of a knot hinders and sometimes even jams translocation. We demonstrate that the probability to do so depends on the protein, the model of the proteasome, the magnitude of the pulling force, and the choice of the pulled terminus. In any case, the net effect would be a hindrance in the proteasomal degradation process in the cell. This would then yield toxicity \textit{via} two different mechanisms: one through toxic monomers compromising degradation and another by the formation of toxic oligomers. Our work paves the way to the mechanistic investigation of the mechanical unfolding of knotted structures by the proteasome and its relation to toxicity and disease.

q-bio.BM↗

arXiv2016

Stiffness of the C-terminal disordered linker affects the geometry of the active site in endoglucanase Cel8A

Cellulosomes are complex multi-enzyme machineries which efficiently degrade plant cell-wall polysaccharides. The multiple domains of the cellulosome proteins are often tethered together by intrinsically disordered regions. The properties and functions of these disordered linkers are not well understood. In this work, we study endoglucanase Cel8A, which is a relevant enzymatic component of the cellulosomes of Clostridium thermocellum. We use both all-atom and coarse-grained simulations to investigate how the equilibrium conformations of the catalytic domain of Cel8A are affected by the disordered linker at its C terminus. We find that when the endoglucanase is bound to its substrate, the effective stiffness of the linker can influence the distances between groups of amino-acid residues throughout the entire enzymatic domain. In particular, variations in the linker stiffness can lead to small changes in the geometry of the active-site cleft. We suggest that such geometrical changes may, in turn, have an effect on the catalytic activity of the enzyme.

q-bio.BM↗

arXiv2016

Criteria for folding in structure-based models of proteins

In structure-based models of proteins, one often assumes that folding is accomplished when all contacts are established. This assumption may frequently lead to a conceptual problem that folding takes place in a temperature region of very low thermodynamic stability, especially when the contact map used is too sparse. We consider six different structure-based models and show that allowing for a small, but model-dependent, percentage of the native contacts not being established boosts the folding temperature substantially while affecting the time scales of folding only in a minor way. We also compare other properties of the six models. We show that the choice of the description of the backbone stiffness has a substantial effect on the values of characteristic temperatures that relate both to equilibrium and kinetic properties. Models without any backbone stiffness (like the self-organized polymer) are found to perform similar to those with the stiffness, including in the studies of stretching.

q-bio.BM↗

arXiv2015

Multiple folding pathways of proteins with shallow knots and co-translational folding

We study the folding process in the shallowly knotted protein MJ0366 within two variants of a structure-based model. We observe that the resulting topological pathways are much richer than identified in previous studies. In addition to the single knot-loop events, we find novel, and dominant, two-loop mechanisms. We demonstrate that folding takes place in a range of temperatures and the conditions of most successful folding are at temperatures which are higher than those required for the fastest folding. We also demonstrate that nascent conditions are more favorable to knotting than off-ribosome folding.

physics.bio-ph↗

arXiv2015

Cotranslational folding of deeply knotted proteins

Proper folding of deeply knotted proteins has a very low success rate even in structure-based models which favor formation of the native contacts but have no topological bias. By employing a structure-based model, we demonstrate that cotranslational folding on a model ribosome may enhance the odds to form trefoil knots for protein YibK without any need to introduce any non-native contacts. The ribosome is represented by a repulsive wall that keeps elongating the protein. On-ribosome folding proceeds through a a slipknot conformation. We elucidate the mechanics and energetics of its formation. We show that the knotting probability in on-ribosome folding is a function of temperature and that there is an optimal temperature for the process. Our model often leads to the establishment of the native contacts without formation of the knot.

physics.bio-ph↗

arXiv2015

Unbinding and unfolding of adhesion protein complexes through stretching: Interplay between shear and tensile mechanical clamps

Using coarse-grained molecular dynamics simulations, we analyze mechanically induced dissociation and unfolding of the protein complex CD48-2B4. This heterodimer is an indispensable component of the immunological system: 2B4 is a receptor on natural killer cells whereas CD48 is expressed on surfaces of various immune cells. So far, its mechanostability has not been assessed either experimentally or theoretically. We find that the dissociation processes strongly depend on the direction of pulling and may take place in several pathways. Interestingly, the CD48-2B4 interface can be divided into three distinct patches that act as units when resisting the pulling forces. At experimentally accessible pulling speeds, the characteristic mechanostability forces are in the range between 100 and 200 pN, depending on the pulling direction. These characteristic forces need not be associated with tensile forces involved in the act of separation of the complex because prior shear-involving unraveling within individual proteins may give rise to a higher force peak.

q-bio.BM↗

arXiv2015

Citrate synthase proteins in extremophilic organisms: Studies within a structure-based model

We study four citrate synthase homodimeric proteins within a structure-based coarse-grained model. Two of these proteins come from thermophilic bacteria, one from a cryophilic bacterium and one from a mesophilic organism; three are in the closed and two in the open conformations. Even though the proteins belong to the same fold, the model distinguishes the properties of these proteins in a way which is consistent with experiments. For instance, the thermophilic proteins are more stable thermodynamically than their mesophilic and cryophilic homologues, which we observe both in the magnitude of thermal fluctuations near the native state and in the kinetics of thermal unfolding. The level of stability correlates with the average coordination number for amino acids contacts and with the degree of structural compactness. The pattern of positional fluctuations along the sequence in the closed conformation is different than in the open conformation, including within the active site. The modes of correlated and anticorrelated movements of pairs of amino acids forming the active site are very different in the open and closed conformations. Taken together, our results show that the precise location of amino acid contacts in the native structure appears to be a critical element in explaining the similarities and differences in the thermodynamic properties, local flexibility and collective motions of the different forms of the enzyme.

q-bio.BM↗

arXiv2014

Aqueous Amino Acids and Proteins Near the Surface of Gold in Hydrophilic and Hydrophobic Force Fields

We calculate potentials of the mean force for twenty amino acids in the vicinity of the (111) surface of gold, for several dipeptides, and for some analogs of the side chains, using molecular dynamics simulations and the umbrella sampling method. We compare results obtained within three different force fields: one hydrophobic (for a contaminated surface) and two hydrophilic. All of these fields lead to good binding with very different specificities and different patterns in the density and polarization of water. The covalent bond with the sulfur atom on cysteine is modeled by the Morse potential. We demonstrate that binding energies of dipeptides are different than the combined binding energies of their amino-acidic components. For the hydrophobic gold, adsorption events of a small protein are driven by attraction to the strongest binding amino acids. This is not so in the hydrophilic cases - a result of smaller specificities combined with the difficulty for proteins, but not for single amino acids, to penetrate the first layer of water. The properties of water near the surface sensitively depend on the force field.

q-bio.BM↗

arXiv2014

Amino acids and proteins at ZnO-water interfaces in molecular dynamics simulations

We determine potentials of the mean force for interactions of amino acids with four common surfaces of ZnO in aqueous solutions. The method involves all-atom molecular dynamics simulations combined with the umbrella sampling technique. The profiled nature of the density of water with the strongly adsorbed first layer affects the approach of amino acids to the surface and generates either repulsion or weak binding. The largest binding energy is found for tyrosine interacting with the surface in which the Zn ions are at the top. It is equal to 7 kJ/mol which is comparable to that of the hydrogen bonds in a protein. This makes the adsorption of amino acids onto the ZnO surface much weaker than onto the well studied surface of gold. Under vacuum, binding energies are more than 40 times stronger (for one of the surfaces). The precise manner in which water molecules interact with a given surface influences the binding energies in a way that depends on the surface. Among the four considered surfaces the one with Zn at the top is recognized as binding almost all amino acids with an average binding energy of 2.60 kJ/mol. Another (O at the top) is non-binding for most amino acids. For binding situations the average energy is 0.66 kJ/mol. The remaining two surfaces bind nearly as many amino acids as they do not and the average binding energies are 1.46 and 1.22 kJ/mol. For all of the surfaces the binding energies vary between amino acids significantly: the dispersion in the range of 68-154% of the mean. A small protein is shown to adsorb onto ZnO only intermittently and with only a small deformation. Various adsorption events lead to different patterns in mobilities of amino acids within the protein.

q-bio.BM↗

arXiv2014

Interactions of aqueous amino acids and proteins with the (110) surface of ZnS in molecular dynamics simulations

The growing usage of nanoparticles of zinc sulfide as quantum dots and biosensors calls for a theoretical assessment of interactions of ZnS with biomolecules. We employ the molecular-dynamics-based umbrella sampling method to determine potentials of mean force for 20 single amino acids near the ZnS (110) surface in aqueous solutions. We find that five amino acids do not bind at all and the binding energy of the remaining amino acids does not exceed 4.3 kJ/mol. Such energies are comparable to those found for ZnO (and to hydrogen bonds in proteins) but the nature of the specificity is different. Cysteine can bind with ZnS in a covalent way, e.g. by forming the disulfide bond with S in the solid. If this effect is included within a model incorporating the Morse potential, then the potential well becomes much deeper - the binding energy is close to 98 kJ/mol. We then consider tryptophan cage, a protein of 20 residues, and characterize its events of adsorption to ZnS. We demonstrate the relevance of interactions between the amino acids in the selection of optimal adsorbed conformations and recognize the key role of cysteine in generation of lasting adsorption. We show that ZnS is more hydrophobic than ZnO and that the density profile of water is quite different than that forming near ZnO - it has only a minor articulation into layers. Furthermore, the first layer of water is disordered and mobile.

q-bio.BM↗