Organizational Unit:

School of Biological Sciences

Permanent Link

https://hdl.handle.net/1853/70750

Parent Organization

Organizational Unit

College of Sciences

Includes Organization(s)

Organizational Unit

Center for the Study of Systems Biology

ArchiveSpace Name Record

https://finding-aids.library.gatech.edu/agents/corporate_entities/1131

Full item page

Publication Search Results

Now showing 1 - 10 of 29

Unfolding of globular proteins: monte carlo dynamics of a realistic reduced model

(Georgia Institute of Technology, 2003-11) Kolinski, Andrzej ; Klein, Piotr ; Romiszowski, Piotr ; Skolnick, Jeffrey

Reduced lattice models of proteins and Monte Carlo dynamics were used to simulate the initial stages of the unfolding of several proteins of various structural types, and the results were compared to experiment. The models semiquantitatively reproduce the approximate order of events of unfolding as well as subtle mutation effects and effects resulting from differences in sequences of similar folds. The short-time mobility of particular residues, observed in simulations, correlates with the crystallographic temperature factor. The main factor controlling unfolding is the native state topology, with sequence playing a less important role. The correlation with various experiments, especially for sequence-specific effects, strongly suggests that properly designed reduced models of proteins can be used for qualitative studies (or prediction) of protein unfolding pathways
TOUCHSTONE II: a new approach to ab initio protein structure prediction

(Georgia Institute of Technology, 2003-08) Zhang, Yang ; Kolinski, Andrzej ; Skolnick, Jeffrey

We have developed a new combined approach for ab initio protein structure prediction. The protein conformation is described as a lattice chain connecting Ca atoms, with attached Cb atoms and side-chain centers of mass. The model force field includes various short-range and long-range knowledge-based potentials derived from a statistical analysis of the regularities of protein structures. The combination of these energy terms is optimized through the maximization of correlation for 30 3 60,000 decoys between the root mean square deviation (RMSD) to native and energies, as well as the energy gap between native and the decoy ensemble. To accelerate the conformational search, a newly developed parallel hyperbolic sampling algorithm with a composite movement set is used in the Monte Carlo simulation processes. We exploit this strategy to successfully fold 41/100 small proteins (36 ; 120 residues) with predicted structures having a RMSD from native below 6.5 A˚ in the top five cluster centroids. To fold larger-size proteins as well as to improve the folding yield of small proteins, we incorporate into the basic force field side-chain contact predictions from our threading program PROSPECTOR where homologous proteins were excluded from the data base. With these threading-based restraints, the program can fold 83/125 test proteins (36 ; 174 residues) with structures having a RMSD to native below 6.5 A˚ in the top five cluster centroids. This shows the significant improvement of folding by using predicted tertiary restraints, especially when the accuracy of side-chain contact prediction is [20%. For native fold selection, we introduce quantities dependent on the cluster density and the combination of energy and free energy, which show a higher discriminative power to select the native structure than the previously used cluster energy or cluster size, and which can be used in native structure identification in blind simulations. These procedures are readily automated and are being implemented on a genomic scale.
A minimal physically realistic protein-like lattice model: designing an energy landscape that ensures all-or-none folding to a unique native state

(Georgia Institute of Technology, 2003-03) Pokarowski, Piotr ; Kolinski, Andrzej ; Skolnick, Jeffrey

A simple protein model restricted to the face-centered cubic lattice has been studied. The model interaction scheme includes attractive interactions between hydrophobic (H) residues, repulsive interactions between hydrophobic and polar (P) residues, and orientation-dependent P-P interactions. Additionally, there is a potential that favors extended b-type conformations. A sequence has been designed that adopts a native structure, consisting of an antiparallel, six-member Greekkey b-barrel with protein-like structural degeneracy. It has been shown that the proposed model is a minimal one, i.e., all the above listed types of interactions are necessary for cooperative (all-or-none) type folding to the native state. Simulations were performed via the Replica Exchange Monte Carlo method and the numerical data analyzed via a multihistogram method.
Numerical study of the entropy loss of dimerization and the folding thermodynamics of the GCN4 leucine zipper

(Georgia Institute of Technology, 2002-11) Viñals, Jorge ; Kolinski, Andrzej ; Skolnick, Jeffrey

A lattice-based model of a protein and the Monte Carlo simulation method are used to calculate the entropy loss of dimerization of the GCN4 leucine zipper. In the representation used, a protein is a sequence of interaction centers arranged on a cubic lattice, with effective interaction potentials that are both of physical and statistical nature. The Monte Carlo simulation method is then used to sample the partition functions of both the monomer and dimer forms as a function of temperature. A method is described to estimate the entropy loss upon dimerization, a quantity that enters the free energy difference between monomer and dimer, and the corresponding dimerization reaction constant. As expected, but contrary to previous numerical studies, we find that the entropy loss of dimerization is a strong function of energy (or temperature), except in the limit of large energies in which the motion of the two dimer chains becomes largely uncorrelated. At the monomer-dimer transition temperature we find that the entropy loss of dimerization is approximately five times smaller than the value that would result from ideal gas statistics, a result that is qualitatively consistent with a recent experimental determination of the entropy loss of dimerization of a synthetic peptide that also forms a two-stranded -helical coiled coil.
Computational studies of protein folding

(Georgia Institute of Technology, 2001-09) Skolnick, Jeffrey ; Kolinski, Andrzej

The authors describe the state of the art in the field of protein structure prediction. They also introduce Prospector, a newly developed, iterative threading algorithm for protein structure prediction that can also be applied to ab initio protein folding, and discuss the promising results of its large-scale application.
Comparison of three Monte Carlo conformational search strategies for a proteinlike homopolymer model: Folding thermodynamics and identification of low-energy structures

(Georgia Institute of Technology, 2000-09-22) Gront, Dominik ; Kolinski, Andrzej ; Skolnick, Jeffrey

Entropy sampling Monte Carlo, the replica method, and the classical Metropolis scheme were applied in numerical studies of the collapse transition in a simple face-centered cubic lattice polymer. The force field of the model consists of pairwise, contact-type, long-range interactions and a short-range potential based on the β -sheet definition assumed in the model. The ability to find the lowest energy conformation by various Monte Carlo methods and the computational cost associated with each was examined. It is shown that all of the methods generally provide the same picture of the collapse transition. However, the most complete thermodynamic description of the transition derives from the results of entropy sampling Monte Carlo simulations, but this is the most time-consuming method. The replica method is shown to be the most effective and efficient in searching for the lowest energy conformation. The possible consequences of these findings for the development of simulation strategies for the folding of model proteins are discussed briefly.
Dynamics and Thermodynamics of β-Hairpin Assembly: Insights from Various Simulation Techniques

(Georgia Institute of Technology, 1999-12) Kolinski, Andrzej ; Ilkowski, Bartosz ; Skolnick, Jeffrey

Small peptides that might have some features of globular proteins can provide important insights into the protein folding problem. Two simulation methods, Monte Carlo Dynamics (MCD), based on the Metropolis sampling scheme, and Entropy Sampling Monte Carlo (ESMC), were applied in a study of a high-resolution lattice model of the C-terminal fragment of the B1 domain of protein G. The results provide a detailed description of folding dynamics and thermodynamics and agree with recent experimental findings (Munoz et al., 1997. Nature. 390:196–197). In particular, it was found that the folding is cooperative and has features of an all-or-none transition. Hairpin assembly is usually initiated by turn formation; however, hydrophobic collapse, followed by the system rearrangement, was also observed. The denatured state exhibits a substantial amount of fluctuating helical conformations, despite the strong b-type secondary structure propensities encoded in the sequence.
De novo simulations of the folding thermodynamics of the GCN4 leucine zipper

(Georgia Institute of Technology, 1999-07) Mohanty, Debasisa ; Kolinski, Andrzej ; Skolnick, Jeffrey

Entropy Sampling Monte Carlo (ESMC) simulations were carried out to study the thermodynamics of the folding transition in the GCN4 leucine zipper (GCN4-lz) in the context of a reduced model. Using the calculated partition functions for the monomer and dimer, and taking into account the equilibrium between the monomer and dimer, the average helix content of the GCN4-lz was computed over a range of temperatures and chain concentrations. The predicted helix contents for the native and denatured states of GCN4-lz agree with the experimental values. Similar to experimental results, our helix content versus temperature curves show a small linear decline in helix content with an increase in temperature in the native region. This is followed by a sharp transition to the denatured state. van’t Hoff analysis of the helix content versus temperature curves indicates that the folding transition can be described using a two-state model. This indicates that knowledge-based potentials can be used to describe the properties of the folded and unfolded states of proteins.
Computer simulations of de novo designed helical proteins

(Georgia Institute of Technology, 1998-07) Sikorski, Andrzej ; Kolinski, Andrzej ; Skolnick, Jeffrey

In the context of reduced protein models, Monte Carlo simulations of three de novo designed helical proteins (four-member helical bundle) were performed. At low temperatures, for all proteins under consideration, protein-like folds having different topologies were obtained from random starting conformations. These simulations are consistent with experimental evidence indicating that these de novo designed proteins have the features of a molten globule state. The results of Monte Carlo simulations suggest that these molecules adopt four-helix bundle topologies. They also give insight into the possible mechanism of folding and association, which occurs in these simulations by on-site assembly of the helices. The low-temperature conformations of all three sequences have the features of a molten globule state.
Monte Carlo studies of the thermodynamics and kinetics of reduced protein models: Application to small helical, β, and α / β proteins

(Georgia Institute of Technology, 1998-02-08) Kolinski, Andrzej ; Galazka, Wojciech ; Skolnick, Jeffrey

Employing a high coordination lattice model and conformational sampling based on dynamic and entropy sampling Monte Carlo protocols, computer experiments were performed on three small globular proteins, each representing one of the three secondary structure classes. The goal was to explore the thermodynamic character of the conformational transition and possible mechanisms of topology assembly. Depending on the stability of isolated elements of secondary structure, topology assembly can proceed by various mechanisms. For the three-helix bundle, protein A, which exhibits substantial helix content in the denatured state, a diffusion–collision mechanism of topology assembly dominates, and here, the conformational transition is predicted to be continuous. In contrast, a model β protein, which possesses little intrinsic denatured state secondary structure, exhibits a sequential "on-site" assembly mechanism and a conformational transition that is well described by a two-state model. Augmenting the cooperativity of tertiary interactions led to a slight shift toward the diffusion–collision model of assembly. Finally, simulations of the folding of the α / β protein G, while only partially successful, suggest that the C-terminal β hairpin should be an early folding conformation and that the N-terminal β hairpin is considerably less stable in isolation. Implications of these results for our general understanding of the process of protein folding and their utility for de novo structure prediction are briefly discussed.