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Center for the Study of Systems Biology

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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.
Optimization of protein structure on lattices using a self-consistent field approach

(Georgia Institute of Technology, 1998) Reva, Boris A. ; Rykunov, D. S. ; Finkelstein, Alexei V. ; Skolnick, Jeffrey

Lattice modeling of proteins is commonly used to study the protein folding problem. The reduced number of possible conformations of lattice models enormously facilitates exploration of the conformational space. In this work, we suggest a method to search for the optimal lattice models that reproduced the off-lattice structures with minimal errors in geometry and energetics. The method is based on the self-consistent field optimization of a combined pseudoenergy function that includes two force fields: an "interaction field," that drives the residues to optimize the chain energy, and a "geometrical field," that attracts the residues towards their native positions. By varying the contributions ofthese force fields in the combined pseudoenergy, one can also test the accuracy of potentials: the better the potentials, i.e., the more accurate the "interaction field," and the smaller the contribution of the "geometrical field" required for building accurate lattice models
Determinants of secondary structure of polypeptide chains: Interplay between short range and burial interactions

(Georgia Institute of Technology, 1997-07-15) Kolinski, Andrzej ; Skolnick, Jeffrey

The effect of tertiary interactions on the observed secondary structure found in the native conformation of globular proteins was examined in the context of a reduced protein model. Short-range interactions are controlled by knowledge based statistical potentials that reflect local conformational regularities seen in a database of three-dimensional protein structures. Long-range interactions are approximated by mean field, single residue based, centrosymmetric hydrophobic burial potentials. Even when pairwise specific long-range interactions are ignored, the inclusion of such burial preferences noticeably modifies the equilibrium chain conformations, and the observed secondary structure is closer to that seen in the folded state. For a test set of 10 proteins (belonging to various structural classes), the accuracy of secondary structure prediction is about 66% and increases by 9% with respect to a related model based on short-range interactions alone [Kolinski et al., J. Chem. Phys. 103, 4312 (1995)]. The increased accuracy is due to the interplay between the short-range conformational propensities and the burial and compactness requirements built into the present model. While the absolute level of accuracy assessed on a per residue basis is comparable to more standard techniques, in contrast to these approaches, the conformation of the chain now has a better defined geometric context. For example, the assumed spherical domain protein model that simulates the segregation of residues between the hydrophobic core and the hydrophilic surface allows for the prediction of surface loops/turns where the polypeptide chain changes its direction. The implications of having such self-consistent secondary structure predictions for the prediction of protein tertiary structure are briefly discussed.
A hierarchical approach to the prediction of the quaternary structure of GCN4 and its mutants

(Georgia Institute of Technology, 1996) Vieth, Michal ; Kolinski, Andrzej ; Brooks, C. L., III ; Skolnick, Jeffrey

A hierarchical approach to protein folding is employed to examine the folding pathway and predict the quaternary structure of the GCN4 leucine zipper. Structures comparable in quality to experiment have been predicted. In addition, the equilibrium between dimers, trimers and tetramers of a number of GCN4 mutants has been examined. In five out of eight cases, the simulation results are in accordance with the experimental studies of Harbury, et al.
Computer design of idealized β-motifs

(Georgia Institute of Technology, 1995-12-15) Kolinski, Andrzej ; Galazka, Wojciech ; Skolnick, Jeffrey

A lattice model of protein conformation and dynamics is used to explore the requirements for the de novo folding from an arbitrary random coil state of idealized models of four and six-member β-barrels. A number of possible conjectures for the factors giving rise to the structural uniqueness of globular proteins are examined. These include the relative role of generic hydrophilic/ hydrophobic amino acid patterns, the relative importance of the specific identity of the hydrophobic amino acids that form the core of the protein and the possible role played by polar groups in destabilizing alternative, misfolded conformations. These studies may also provide some insights into the relative importance of short range interactions, cooperative hydrogen bonding and tertiary interactions in determining the uniqueness of the native state, as well as the cooperativity of the folding process. Thus, these simulations may provide guidelines for the early stages of the protein design process. Possible applications to the general protein folding problem are also briefly discussed.
A Monte Carlo model of fd and Pf1 coat proteins in lipid membranes

(Georgia Institute of Technology, 1995-10) Milik, Mariusz ; Skolnick, Jeffrey

A Monte Carlo Dynamics simulation was used to investigate the behavior of filamentous bacteriophage coat proteins in a model membrane environment. Our simulation agrees with the previous experimental observations that despite the low sequence similarity between the major coat proteins of Pf1 and fd bacteriophages, their structure in the membrane environment is very similar. These results support the hypothesis that the hydrophobic effect exerts an important influence on membrane protein structure. The model may also be used for modeling the insertion and transport processes in protein-membrane systems. The example of fd protein was also used as a test of sensitivity of our model to temperature, thickness of the hydrocarbon phase, and simulation time. In all cases, the results were independent (over the tested range) of the particular values of the parameters.
A reduced model of short range interactions in polypeptide chains

(Georgia Institute of Technology, 1995-09-08) Kolinski, Andrzej ; Milik, Mariusz ; Rycombel, Jakub ; Skolnick, Jeffrey

A simple model of short range interactions is proposed for a reduced lattice representation of polypeptide conformation. The potential is derived on the basis of statistical regularities seen in the known crystal structures of globular proteins. This potential accounts for the generic stiffness of polypeptides, the correlation between peptide bond plates, and the sequence dependent correlations between consecutive segments of the C-trace. This model is used for simulation of the equilibrium and dynamic properties of polypeptides in the denatured state. It is shown that the proposed factorization of the local conformational propensities reproduces secondary structure tendencies encoded in the protein sequence. Possible applications for modeling of protein folding are briefly discussed.