United-residue Force Field Research Articles

Insight into the Initial Stages of the Folding Process in Onconase Revealed by UNRES.

The unfolded state of proteins presents many challenges to elucidate the structural basis for biological function. This state is characterized by a large degree of structural heterogeneity which makes it difficult to generate structural models. However, recent experiments into the initial folding events of the 104-residue ribonuclease homologue onconase (ONC) were able to identify the regions in the protein that participate in the initial folding of this protein. Therefore, to gain additional structural insight into the unfolded state of proteins, this study utilized molecular dynamics simulations using the UNited-RESidue (UNRES) force field to evaluate whether there is a good agreement between the experimentally determined initial structures and the structures identified by computer simulations along a folding pathway. Indeed, these UNRES simulations accurately identified the two regions experimentally observed to form the initial native structure along the folding pathway of ONC. In addition, these regions are determined to be chain folding initiation sites (CFIS) according to methods developed previously. Subsequent self-organization maps (SOM) analysis has revealed key structural states involved in these early folding events.

Mechanistic Kinetic Model Reveals How Amyloidogenic Hydrophobic Patches Facilitate the Amyloid-β Fibril Elongation.

Abnormal aggregation of amyloid β (Aβ) peptides into fibrils plays a critical role in the development of Alzheimer's disease. A two-stage "dock-lock" model has been proposed for the Aβ fibril elongation process. However, the mechanisms of the Aβ monomer-fibril binding process have not been elucidated with the necessary molecular-level precision, so it remains unclear how the lock phase dynamics leads to the overall in-register binding of the Aβ monomer onto the fibril. To gain mechanistic insights into this critical step during the fibril elongation process, we used molecular dynamics (MD) simulations with a physics-based coarse-grained UNited-RESidue (UNRES) force field and sampled extensively the dynamics of the lock phase process, in which a fibril-bound Aβ(9-40) peptide rearranged to establish the native docking conformation. Analysis of the MD trajectories with Markov state models was used to quantify the kinetics of the rearrangement process and the most probable pathways leading to the overall native docking conformation of the incoming peptide. These revealed a key intermediate state in which an intra-monomer hairpin is formed between the central core amyloidogenic patch 18VFFA21 and the C-terminal hydrophobic patch 34LMVG37. This hairpin structure is highly favored as a transition state during the lock phase of the fibril elongation. We propose a molecular mechanism for facilitation of the Aβ fibril elongation by amyloidogenic hydrophobic patches.

Modeling the Structure, Dynamics, and Transformations of Proteins with the UNRES Force Field.

The physics-based united-residue (UNRES) model of proteins ( www.unres.pl ) has been designed to carry out large-scale simulations of protein folding. The force field has been derived and parameterized based on the principles of statistical-mechanics, which makes it independent of structural databases and applicable to treat nonstandard situations such as, proteins that contain D-amino-acid residues. Powered by Langevin dynamics and its replica-exchange extensions, UNRES has found a variety of applications, including ab initio and database-assisted protein-structure prediction, simulating protein-folding pathways, exploring protein free-energy landscapes, and solving biological problems. This chapter provides a summary of UNRES and a guide for potential users regarding the application of the UNRES package in a variety of research tasks.

Investigation of Phosphorylation-Induced Folding of an Intrinsically Disordered Protein by Coarse-Grained Molecular Dynamics.

Apart from being the most common mechanism of regulating protein function and transmitting signals throughout the cell, phosphorylation has an ability to induce disorder-to-order transition in an intrinsically disordered protein. In particular, it was shown that folding of the intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can be induced by multisite phosphorylation. Here, the principles that govern the folding of phosphorylated 4E-BP2 (pT37pT46 4E-BP218-62) are investigated by analyzing canonical and replica exchange molecular dynamics trajectories, generated with the coarse-grained united-residue force field, in terms of local and global motions and the time dependence of formation of contacts between Cαs of selected pairs of residues. The key residues involved in the folding of the pT37pT46 4E-BP218-62 are elucidated by this analysis. The correlations between local and global motions are identified. Moreover, for a better understanding of the physics of the formation of the folded state, the experimental structure of the pT37pT46 4E-BP218-62 is analyzed in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrödinger equation. It is shown that without molecular dynamics simulations the kinks are able to identify not only the phosphorylated sites of protein, the key players in folding, but also the reasons for the weak stability of the pT37pT46 4E-BP218-62.

Extension of coarse-grained UNRES force field to treat carbon nanotubes

Carbon nanotubes (CNTs) have recently received considerable attention because of their possible applications in various branches of nanotechnology. For their cogent application, knowledge of their interactions with biological macromolecules, especially proteins, is essential and computer simulations are very useful for such studies. Classical all-atom force fields limit simulation time scale and size of the systems significantly. Therefore, in this work, we implemented CNTs into the coarse-grained UNited RESidue (UNRES) force field. A CNT is represented as a rigid infinite-length cylinder which interacts with a protein through the Kihara potential. Energy conservation in microcanonical coarse-grained molecular dynamics simulations and temperature conservation in canonical simulations with UNRES containing the CNT component have been verified. Subsequently, studies of three proteins, bovine serum albumin (BSA), soybean peroxidase (SBP), and α-chymotrypsin (CT), with and without CNTs, were performed to examine the influence of CNTs on the structure and dynamics of these proteins. It was found that nanotubes bind to these proteins and influence their structure. Our results show that the UNRES force field can be used for further studies of CNT-protein systems with 3–4 order of magnitude larger timescale than using regular all-atom force fields.Graphical abstractBovine serum albumin (BSA), soybean peroxidase (SBP), and α-chymotrypsin (CT), with and without CNTsᅟ

Shielding effect in protein folding

One of the most important interactions responsible for protein folding and stability are hydrogen bonds between peptide groups. There is a constant competition between the water molecules and peptide groups in a hydrogen bond formation. Also side-chains take part in this process by reducing hydration of peptide group (shielding effect) that promotes the protein folding. In this paper, a new approach to take into account a shielding effect is presented. A modification of the energy function is derived and incorporated into the UNited RESidue (UNRES) force field. Canonical Molecular Dynamics and Replica Exchange Molecular Dynamics with UNRES force field is applied to study the influence of this effect on protein structure, folding kinetics and free energy landscapes. The results of test calculations suggest that even small contribution of this effect into energy function changes force field behavior as well as speeds up the folding process significantly.

Simple Physics-Based Analytical Formulas for the Potentials of Mean Force of the Interaction of Amino Acid Side Chains in Water. VII. Charged-Hydrophobic/Polar and Polar-Hydrophobic/Polar Side Chains.

The physics-based potentials of side-chain-side-chain interactions corresponding to pairs composed of charged and polar, polar and polar, charged and hydrophobic, and hydrophobic and hydrophobic side chains have been determined. A total of 144 four-dimensional potentials of mean force (PMFs) of all possible pairs of molecules modeling these pairs were determined by umbrella-sampling molecular dynamics simulations in explicit water as functions of distance and orientation, and the analytical expressions were then fitted to the PMFs. Depending on the type of interacting sites, the analytical approximation to the PMF is a sum of terms corresponding to van der Waals interactions and cavity-creation involving the nonpolar sections of the side chains and van der Waals, cavity-creation, and electrostatic (charge-dipole or dipole-dipole) interaction energies and polarization energies involving the charged or polar sections of the side chains. The model used in this work reproduces all features of the interacting pairs. The UNited RESidue force field with the new side-chain-side-chain interaction potentials was preliminarily tested with the N-terminal part of the B-domain of staphylococcal protein A (PDBL 1BDD ; a three-α-helix bundle) and UPF0291 protein YnzC from Bacillus subtilis (PDB: 2HEP ; an α-helical hairpin).

Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics.

Fibrils formed by the β-amyloid (Aβ) peptide play a central role in the development of Alzheimer's disease. In this study, the principles governing their growth and stability are investigated by analyzing canonical and replica-exchange molecular dynamics trajectories of Aβ(9-40) fibrils. In particular, an unstructured monomer was allowed to interact freely with an Aβ fibril template. Trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle θ and backbone virtual-bond-dihedral angle γ of each residue and principal components, respectively, were analyzed. Also, thermal unbinding (unfolding) of an Aβ peptide from the fibril template was investigated. These analyses enable us to illustrate the entire process of Aβ fibril elongation and to elucidate the key residues involved in it. Several different pathways were identified during the search for the fibril conformation by the monomer, which finally follows a dock-lock mechanism with two distinct locking stages. However, it was found that the correct binding, with native hydrogen bonds, of the free monomer to the fibril template at both stages is crucial for fibril elongation. In other words, if the monomer is incorrectly bound (with nonnative hydrogen bonds) to the fibril template during the first "docking" stage, it can remain attached to it for a long time before it dissociates and either attempts a different binding or allows another monomer to bind. This finding is consistent with an experimentally observed "stop-and-go" mechanism of fibril growth.

Use of Restraints from Consensus Fragments of Multiple Server Models To Enhance Protein-Structure Prediction Capability of the UNRES Force Field.

Recently, we developed a new approach to protein-structure prediction, which combines template-based modeling with the physics-based coarse-grained UNited RESidue (UNRES) force field. In this approach, restrained multiplexed replica exchange molecular dynamics simulations with UNRES, with the Cα-distance and virtual-bond-dihedral-angle restraints derived from knowledge-based models are carried out. In this work, we report a test of this approach in the 11th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP11), in which we used the template-based models from early-stage predictions by the LEE group CASP11 server (group 038, called "nns"), and further improvement of the method. The quality of the models obtained in CASP11 was better than that resulting from unrestrained UNRES simulations; however, the obtained models were generally worse than the final nns models. Calculations with the final nns models, performed after CASP11, resulted in substantial improvement, especially for multi-domain proteins. Based on these results, we modified the procedure by deriving restraints from models from multiple servers, in this study the four top-performing servers in CASP11 (nns, BAKER-ROSETTASERVER, Zhang-server, and QUARK), and implementing either all restraints or only the restraints on the fragments that appear similar in the majority of models (the consensus fragments), outlier models discarded. Tests with 29 CASP11 human-prediction targets with length less than 400 amino-acid residues demonstrated that the consensus-fragment approach gave better results, i.e., lower α-carbon root-mean-square deviation from the experimental structures, higher template modeling score, and global distance test total score values than the best of the parent server models. Apart from global improvement (repacking and improving the orientation of domains and other substructures), improvement was also reached for template-based modeling targets, indicating that the approach has refinement capacity. Therefore, the consensus-fragment analysis is able to remove lower-quality models and poor-quality parts of the models without knowing the experimental structure.

Folding and Unfolding Simulations of a Three-Stranded Beta-Sheet Protein

Understanding the folding processes of a protein into its three-dimensional native structure only with its amino-acid sequence information is a long-standing challenge in modern science. Two- hundred independent folding simulations (starting from non-native conformations) and two- hundred independent unfolding simulations (starting from the folded native structure) are performed using the united-residue force field and Metropolis Monte Carlo algorithm for betanova (three-stranded antiparallel beta-sheet protein). From these extensive computer simulations, two representative folding pathways and two representative unfolding pathways are obtained in the reaction coordinates such as the fraction of native contacts, the radius of gyration, and the root- mean-square deviation. The folding pathways and the unfolding pathways are similar each other. The largest deviation between the folding pathways and the unfolding pathways results from the root-mean-square deviation near the folded native structure. In general, unfolding computer simulations could capture the essentials of folding simulations.

Prediction of Protein Structure by Template-Based Modeling Combined with the UNRES Force Field.

A new approach to the prediction of protein structures that uses distance and backbone virtual-bond dihedral angle restraints derived from template-based models and simulations with the united residue (UNRES) force field is proposed. The approach combines the accuracy and reliability of template-based methods for the segments of the target sequence with high similarity to those having known structures with the ability of UNRES to pack the domains correctly. Multiplexed replica-exchange molecular dynamics with restraints derived from template-based models of a given target, in which each restraint is weighted according to the accuracy of the prediction of the corresponding section of the molecule, is used to search the conformational space, and the weighted histogram analysis method and cluster analysis are applied to determine the families of the most probable conformations, from which candidate predictions are selected. To test the capability of the method to recover template-based models from restraints, five single-domain proteins with structures that have been well-predicted by template-based methods were used; it was found that the resulting structures were of the same quality as the best of the original models. To assess whether the new approach can improve template-based predictions with incorrectly predicted domain packing, four such targets were selected from the CASP10 targets; for three of them the new approach resulted in significantly better predictions compared with the original template-based models. The new approach can be used to predict the structures of proteins for which good templates can be found for sections of the sequence or an overall good template can be found for the entire sequence but the prediction quality is remarkably weaker in putative domain-linker regions.

My 65 years in protein chemistry.

This is a tour of a physical chemist through 65 years of protein chemistry from the time when emphasis was placed on the determination of the size and shape of the protein molecule as a colloidal particle, with an early breakthrough by James Sumner, followed by Linus Pauling and Fred Sanger, that a protein was a real molecule, albeit a macromolecule. It deals with the recognition of the nature and importance of hydrogen bonds and hydrophobic interactions in determining the structure, properties, and biological function of proteins until the present acquisition of an understanding of the structure, thermodynamics, and folding pathways from a linear array of amino acids to a biological entity. Along the way, with a combination of experiment and theoretical interpretation, a mechanism was elucidated for the thrombin-induced conversion of fibrinogen to a fibrin blood clot and for the oxidative-folding pathways of ribonuclease A. Before the atomic structure of a protein molecule was determined by x-ray diffraction or nuclear magnetic resonance spectroscopy, experimental studies of the fundamental interactions underlying protein structure led to several distance constraints which motivated the theoretical approach to determine protein structure, and culminated in the Empirical Conformational Energy Program for Peptides (ECEPP), an all-atom force field, with which the structures of fibrous collagen-like proteins and the 46-residue globular staphylococcal protein A were determined. To undertake the study of larger globular proteins, a physics-based coarse-grained UNited-RESidue (UNRES) force field was developed, and applied to the protein-folding problem in terms of structure, thermodynamics, dynamics, and folding pathways. Initially, single-chain and, ultimately, multiple-chain proteins were examined, and the methodology was extended to protein-protein interactions and to nucleic acids and to protein-nucleic acid interactions. The ultimate results led to an understanding of a variety of biological processes underlying natural and disease phenomena.

Introduction of periodic boundary conditions into UNRES force field.

In this article, implementation of periodic boundary conditions (PBC) into physics-based coarse-grained UNited RESidue (UNRES) force field is presented, which replaces droplet-like restraints previously used. Droplet-like restraints are necessary to keep multichain systems together and prevent them from dissolving to infinitely low concentration. As an alternative for droplet-like restrains cuboid PBCs with imaging of the molecules were introduced. Owing to this modification, artificial forces which arose from restraints keeping a droplet together were eliminated what leads to more realistic trajectories. Due to computational reasons cutoff and smoothing functions were introduced on the long range interactions. The UNRES force field with PBC was tested by performing microcanonical simulations. Moreover, to asses the behavior of the thermostat in PBCs Langevin and Berendsen thermostats were studied. The influence of PBCs on association pattern was compared with droplet-like restraints on the ββα hetero tetramer 1 protein system.

Physics-based potentials for the coupling between backbone- and side-chain-local conformational states in the UNited RESidue (UNRES) force field for protein simulations.

The UNited RESidue (UNRES) model of polypeptide chains is a coarse-grained model in which each amino-acid residue is reduced to two interaction sites, namely, a united peptide group (p) located halfway between the two neighboring α-carbon atoms (Cαs), which serve only as geometrical points, and a united side chain (SC) attached to the respective Cα. Owing to this simplification, millisecond molecular dynamics simulations of large systems can be performed. While UNRES predicts overall folds well, it reproduces the details of local chain conformation with lower accuracy. Recently, we implemented new knowledge-based torsional potentials (Krupa et al. J. Chem. Theory Comput. 2013, 9, 4620–4632) that depend on the virtual-bond dihedral angles involving side chains: Cα···Cα···Cα···SC (τ(1)), SC···Cα···Cα···Cα (τ(2)), and SC···Cα···Cα···SC (τ(3)) in the UNRES force field. These potentials resulted in significant improvement of the simulated structures, especially in the loop regions. In this work, we introduce the physics-based counterparts of these potentials, which we derived from the all-atom energy surfaces of terminally blocked amino-acid residues by Boltzmann integration over the angles λ(1) and λ(2) for rotation about the Cα···Cα virtual-bond angles and over the side-chain angles χ. The energy surfaces were, in turn, calculated by using the semiempirical AM1 method of molecular quantum mechanics. Entropy contribution was evaluated with use of the harmonic approximation from Hessian matrices. One-dimensional Fourier series in the respective virtual-bond-dihedral angles were fitted to the calculated potentials, and these expressions have been implemented in the UNRES force field. Basic calibration of the UNRES force field with the new potentials was carried out with eight training proteins, by selecting the optimal weight of the new energy terms and reducing the weight of the regular torsional terms. The force field was subsequently benchmarked with a set of 22 proteins not used in the calibration. The new potentials result in a decrease of the root-mean-square deviation of the average conformation from the respective experimental structure by 0.86 Å on average; however, improvement of up to 5 Å was observed for some proteins.

A Coarse-Grained Model to Study Calcium Activation of the Cardiac Thin Filament

Familial hypertrophic cardiomyopathy (FHC) is one of the most common heart disease caused by genetic mutations. Cardiac muscle contraction and relaxation involve regulation of crossbridge binding to the cardiac thin filament, which regulates actomyosin interactions through calcium-dependent alterations in the dynamics of cardiac troponin (cTn) and tropomyosin (Tm). An atomistic model of cTn complex interacting with Tm has been studied by our group. A more realistic model requires the inclusion of the dynamics of actin filament, which is almost 6 times larger than cTn and Tm in terms of atom numbers, and extensive sampling of the model becomes very resource-demanding. By using physics-based protein united-residue force field, we introduce a coarse-grained model to study the calcium activation of the thin filament resulting from cTn's allosteric regulation of Tm dynamics on actin. In the corase-grained system, residues are represented by sidechain ellipsoids (SC) and peptide groups (p). Vectors between adjacent Cα-Cα and Cα-SC are chosen as variables, and the velocity Verlet algorithm is used to derive the equations of motion. The time scale is much longer than that of all-atom molecular dynamics simulation because of the reduction of the degrees of freedom. The coarse-grained model is a good template for studying cardiac thin filament mutations that cause FHC, and reduces the cost of computational resources.

Folding kinetics of WW domains with the united residue force field for bridging microscopic motions and experimental measurements.

To demonstrate the utility of the coarse-grained united-residue (UNRES) force field to compare experimental and computed kinetic data for folding proteins, we have performed long-time millisecond-timescale canonical Langevin molecular dynamics simulations of the triple β-strand from the Formin binding protein 28 WW domain and six nonnatural variants, using UNRES. The results have been compared with available experimental data in both a qualitative and a quantitative manner. Complexities of the folding pathways, which cannot be determined experimentally, were revealed. The folding mechanisms obtained from the simulated folding kinetics are in agreement with experimental results, with a few discrepancies for which we have accounted. The origins of single- and double-exponential kinetics and their correlations with two- and three-state folding scenarios are shown to be related to the relative barrier heights between the various states. The rate constants obtained from time profiles of the fractions of the native, intermediate, and unfolded structures, and the kinetic equations fitted to them, correlate with the experimental values; however, they are about three orders of magnitude larger than the experimental ones for most of the systems. These differences are in agreement with the timescale extension derived by scaling down the friction of water and averaging out the fast degrees of freedom when passing from all-atom to a coarse-grained representation. Our results indicate that the UNRES force field can provide accurate predictions of folding kinetics of these WW domains, often used as models for the study of the mechanisms of proein folding.

Kinks, loops, and protein folding, with protein A as an example.

The dynamics and energetics of formation of loops in the 46-residue N-terminal fragment of the B-domain of staphylococcal protein A has been studied. Numerical simulations have been performed using coarse-grained molecular dynamics with the united-residue (UNRES) force field. The results have been analyzed in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrödinger (DNLS) equation. In the case of proteins, the DNLS equation arises from a C(α)-trace-based energy function. Three individual kink profiles were identified in the experimental three-α-helix structure of protein A, in the range of the Glu16-Asn29, Leu20-Asn29, and Gln33-Asn44 residues, respectively; these correspond to two loops in the native structure. UNRES simulations were started from the full right-handed α-helix to obtain a clear picture of kink formation, which would otherwise be blurred by helix formation. All three kinks emerged during coarse-grained simulations. It was found that the formation of each is accompanied by a local free energy increase; this is expressed as the change of UNRES energy which has the physical sense of the potential of mean force of a polypeptide chain. The increase is about 7 kcal/mol. This value can thus be considered as the free energy barrier to kink formation in full α-helical segments of polypeptide chains. During the simulations, the kinks emerge, disappear, propagate, and annihilate each other many times. It was found that the formation of a kink is initiated by an abrupt change in the orientation of a pair of consecutive side chains in the loop region. This resembles the formation of a Bloch wall along a spin chain, where the C(α) backbone corresponds to the chain, and the amino acid side chains are interpreted as the spin variables. This observation suggests that nearest-neighbor side chain-side chain interactions are responsible for initiation of loop formation. It was also found that the individual kinks are reflected as clear peaks in the principal modes of the analyzed trajectory of protein A, the shapes of which resemble the directional derivatives of the kinks along the chain. These observations suggest that the kinks of the DNLS equation determine the functionally important motions of proteins.

Improvement of the Treatment of Loop Structures in the UNRES Force Field by Inclusion of Coupling between Backbone- and Side-Chain-Local Conformational States

The UNited RESidue (UNRES) coarse-grained model of polypeptide chains, developed in our laboratory, enables us to carry out millisecond-scale molecular-dynamics simulations of large proteins effectively. It performs well in ab initio predictions of protein structure, as demonstrated in the last Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP10). However, the resolution of the simulated structure is too coarse, especially in loop regions, which results from insufficient specificity of the model of local interactions. To improve the representation of local interactions, in this work we introduced new side-chain-backbone correlation potentials, derived from a statistical analysis of loop regions of 4585 proteins. To obtain sufficient statistics, we reduced the set of amino-acid-residue types to five groups, derived in our earlier work on structurally optimized reduced alphabets, based on a statistical analysis of the properties of amino-acid structures. The new correlation potentials are expressed as one-dimensional Fourier series in the virtual-bond-dihedral angles involving side-chain centroids. The weight of these new terms was determined by a trial-and-error method, in which Multiplexed Replica Exchange Molecular Dynamics (MREMD) simulations were run on selected test proteins. The best average root-mean-square deviations (RMSDs) of the calculated structures from the experimental structures below the folding-transition temperatures were obtained with the weight of the new side-chain-backbone correlation potentials equal to 0.57. The resulting conformational ensembles were analyzed in detail by using the Weighted Histogram Analysis Method (WHAM) and Ward's minimum-variance clustering. This analysis showed that the RMSDs from the experimental structures dropped by 0.5 Å on average, compared to simulations without the new terms, and the deviation of individual residues in the loop region of the computed structures from their counterparts in the experimental structures (after optimum superposition of the calculated and experimental structure) decreased by up to 8 Å. Consequently, the new terms improve the representation of local structure.

Local vs Global Motions in Protein Folding

It is of interest to know whether local fluctuations in a polypeptide chain play any role in the mechanism by which the chain folds to the native structure of a protein. This question is addressed by analyzing folding and non-folding trajectories of a protein; as an example, the analysis is applied to the 37-residue triple β-strand WW domain from the Formin binding protein 28 (FBP28) (PDB ID: 1E0L). Molecular dynamics (MD) trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle θ and backbone virtual-bond-dihedral angle γ of each residue, and principal components, respectively, were analyzed. The key residues involved in the folding of the FBP28 WW domain are elucidated by this analysis. The correlations between local and global motions are found. It is shown that most of the residues in the folding trajectories of the system studied here move in a concerted fashion, following the dynamics of the whole system. This demonstrates how the choice of a pathway has to involve concerted movements in order for this protein to fold. This finding also sheds light on the effectiveness of principal component analysis (PCA) for the description of the folding dynamics of the system studied. It is demonstrated that the FEL along the PCs, computed by considering only several critically-placed residues, can correctly describe the folding dynamics.

MOLECULAR DYNAMICS SIMULATIONS OF HELIX BUNDLE PROTEINS USING UNRES FORCE FIELD AND ALL-ATOM FORCE FIELD

We have investigated the folding of two helix-bundle proteins, 36-residue Villin headpiece and 56-residue E-domain of Staphylococcal protein A, by combining molecular dynamics (MD) simulations with Coarse-Grained United-Residue (UNRES) Force Field and all-atom force field. Starting from extended structures, each of the proteins was folded to a stable structure within a short time frame using the UNRES model. However, the secondary structures of helices were not well formed. Further refinement using MD simulations with the all-atom force field was able to fold the protein structure into the native-like state with the smallest main-chain root-mean-square deviation of around 3 Å. Detailed analysis of the folding trajectories was presented and the performance of GPU-based MD simulations was also discussed.