PubMed Health⌕ Search

Biomedical subjects

A M Gutin

Publications and source records attributed to A M Gutin.

At least 19 recordsLinked to original sources
PubMed1998

Theory of kinetic partitioning in protein folding with possible applications to prions.

This study focuses of the phenomenon of kinetic partitioning when a polypeptide chain has two ground-state conformations, one of which is kinetically more reachable than the other. We designed sequences for lattice model proteins with two different conformations of equal energy corresponding to the global energy minimum. Folding simulations revealed that one of these conformations was indeed much more kinetically accessible than the other. We found that the number and strength of local contacts in the ground-state conformation are the major factors that determine which conformation is reached faster; the greater the number of local contacts, the more kinetically reachable a conformation is. We present simple statistical-mechanical arguments to explain these findings. Our results may be relevant in explaining the phenomenology of such proteins as human plasminogen activator inhibitor-1 (PAI-1), photosystem II, and prions.

Amino Acid Sequence↗
PubMed1998

A protein engineering analysis of the transition state for protein folding: simulation in the lattice model.

BACKGROUND: Protein engineering has been used extensively to evaluate the properties of transition states in protein folding. Although the method has proved useful, its limitations and the details of interpretation of the obtained results remain largely unexplored. RESULTS: Lattice model simulations are used to test and verify the protein engineering analysis of the transition state in protein folding. It is shown that in some cases - but not always - this method is able to determine the transition state with reasonable accuracy. Limitations of protein engineering are revealed and analyzed. In particular, the change in non-native interactions as a result of mutations is shown to influence the results of the protein engineering analysis. Furthermore, the temperature dependencies of phi values (which are a measure of the participation of a residue in the transition state) and the character of the transition state ensemble are studied. It is shown that as a general trend phi values decrease when the temperature decreases, a finding consistent with recent experimental results. Our analysis suggests that this trend results primarily from the formation of some contacts (native and non-native) in the unfolded state at a lower temperature, when the barrier for folding is energetic. CONCLUSIONS: Our analysis helps to interpret the results of protein engineering and allows observed φ values to be directly related to structural features of the unfolded state, the transition state and the native state.

Amino Acid Sequence↗
PubMed1997

Computer simulations of prebiotic evolution.

This paper is a review of our previous work on the field of possible ways of prebiotic evolution. We propose an algorithm providing sequences of model proteins with rapid folding into a given native conformation. Thermodynamical analysis shows that the increase in speed is matched by an increase in stability: the evolved sequences are much more stable in their native conformation than the initial random sequence. We discuss a possible origin of the first biopolymers, having stable unique structure. We suggest that at the prebiotic stage of evolution, long organic polymers had to be compact in order to avoid hydrolysis and had to be soluble and thus must not be exceedingly hydrophobic. We present an algorithm that generates such sequences of model proteins. The evolved sequences turn out to have a stable unique structure, into which they quickly fold. This result illustrates the idea that the unique three-dimensional native structure of first biopolymers could have evolved as a side effect of a nonspecific physico-chemical factors acting at the prebiotic stage of evolution.

Algorithms↗
PubMed1996

How the first biopolymers could have evolved.

In this work, we discuss a possible origin of the first biopolymers with stable unique structures. We suggest that at the prebiotic stage of evolution, long organic polymers had to be compact to avoid hydrolysis and had to be soluble and thus must not be exceedingly hydrophobic. We present an algorithm that generates such sequences for model proteins. The evolved sequences turn out to have a stable unique structure, into which they quickly fold. This result illustrates the idea that the unique three-dimensional native structures of first biopolymers could have evolved as a side effect of nonspecific physicochemical factors acting at the prebiotic stage of evolution.

Algorithms↗
PubMed1996

Simulations of chaperone-assisted folding.

We investigated a chaperone mechanism of protein folding using a 36-mer model on a cubic lattice. The mechanism simulates folding, which proceeds with repetitive cycles of binding, unfolding, and releasing of misfolded metastable states. We measured the yield enhancement due to this mechanism for sequences selected by evolutionary design and showed that the binding and releasing mechanism is efficient for the yield enhancement of folding for sequences that are poorly designed, i.e., where selection is not adequately strong. From this it follows that the chaperone mechanism can be considered as the evolutionary alternative to compensate for poor sequence design. On the other hand, random sequences show a decrease in yield and no effect on the total mean first passage time when the proposed chaperone mechanism is implemented, thus implying that sequence optimization is a necessary condition for the efficiency of the proposed mechanism. We qualitatively reproduced experimental results for folding in the presence of GroEL/GroES, fit our results with the aid of a double-exponential model of folding kinetics, and characterized the conditions under which this mechanism of chaperone action affects folding.

Amino Acid Sequence↗
PubMed1996

Improved design of stable and fast-folding model proteins.

BACKGROUND: A number of approaches to design stable and fast-folding sequences for model polypeptide chains have been based on the premise that optimization of the relative energy of the native conformation (or Z-score) is sufficient to yield stable and fast-folding sequences. Although this approach has been successful, for longer chains it often yielded sequences that failed to fold cooperatively, instead having multidomain folding behavior. RESULTS: We show that one of the factors determining single-domain or multidomain folding behavior is the dispersion of energies of native contacts. So, we study folding of sequences optimized to have the same native conformation as a global energy minimum but having different dispersion of native contact energies. Our results suggest that under conditions at which native conformation is stable, the best-folding proteins are those that have smaller heterogeneity of native contact energies. For them, the folding transition is all-or-none. On the other hand, proteins with greater heterogeneity of native contact energies have more gradual multidomain folding transition and fold into stable native conformation much slower than those proteins with small dispersion of native contact energies.

Amino Acid Sequence↗
PubMed1995

Impact of local and non-local interactions on thermodynamics and kinetics of protein folding.

To address the question of how the geometry of a protein's native conformation affects its folding and stability, we studied three model 36-mers on a cubic lattice. The native structure of one of these model 36-mers consisted mostly of local contacts, while that of a second consisted mostly of non-local contacts. The third native structure had a typical compact native conformation, and served as our reference. For each protein, the amino acid sequence was designed to have a pronounced energy minimum at its native conformation. We observed dramatic differences in folding, dependent on the presence or absence of non-local contacts. For the proteins with a typical large number of non-local contacts, the folding transition was all-or-none, whereas for the one with mostly local contacts, it was not. Although the maximum rate of folding was similar for all three proteins, we found that under conditions at which each native conformation was stable, the structure with mostly non-local contacts folded two orders of magnitude faster than the one with mostly local contacts. The statistical analysis of protein structure agrees fully with the implications of the theory. We discuss the importance of cooperativity in protein folding for its stability.

Amino Acid Sequence↗
PubMed1995

Is burst hydrophobic collapse necessary for protein folding?

Folding of the lattice model of proteins is studied using Monte Carlo simulation. The amino acid sequence is designed to have a pronounced energy minimum for a given target (native) conformation. Our simulations reveal two possible scenarios. When the overall attraction between residues dominates, we find that folding to the native conformation is preceded by a rapid collapse into a burst intermediate which is a compact but structureless globule. Then, after a much longer time, an all-or-none transition from the globule to the native conformation occurs. In contrast, when the overall attraction is not strong, we do not observe a burst collapse stage. Instead, we find an all-or-none transition directly from the coil to the native conformation. Both scenarios yield comparable rates of folding. On the basis of these findings we discuss the role of intermediates in thermodynamics and kinetics of protein folding.

Amino Acid Sequence↗
PubMed1995

Evolution-like selection of fast-folding model proteins.

We propose an algorithm providing sequences of model proteins with rapid folding into a given target (native) conformation. This algorithm is applied to a chain of 27 residues on a cubic lattice. It generates sequences with folding 2 orders of magnitude faster than that of the practically random starting sequence. Thermodynamic analysis shows that the increase in speed is matched by an increase in stability: the evolved sequences are much more stable in their native conformation than the initial random sequence. The unfolding temperature for evolved sequences is slightly higher than the simulation temperature, bearing direct correspondence to the relatively low stability of real proteins.

Algorithms↗
PubMed1995

Domains in folding of model proteins.

By means of Monte Carlo simulation, we investigated the equilibrium between folded and unfolded states of lattice model proteins. The amino acid sequences were designed to have pronounced energy minimum target conformations of different length and shape. For short fully compact (36-mer) proteins, the all-or-none transition from the unfolded state to the native state was observed. This was not always the case for longer proteins. Among 12 designed sequences with the native structure of a fully compact 48-mer, a simple all-or-none transition was observed in only three cases. For the other nine sequences, three states of behavior-the native, denatured, and intermediate states-were found. The contiguous part of the native structure (domain) was conserved in the intermediate state, whereas the remaining part was completely unfolded and structureless. These parts melted separately from each other.

Amino Acid Sequence↗
PubMed1995

Why do protein architectures have Boltzmann-like statistics?

A theoretical study has shown that the occurrence of various structural elements in stable folds of random copolymers is exponentially dependent on the own energy of the element. A similar occurrence-on-energy dependence is observed in globular proteins from the level of amino acid conformations to the level of overall architectures. Thus, the structural features stabilized by many random sequences are typical of globular proteins while the features rarely observed in proteins are those which are stabilized by only a minor part of the random sequences.

Computer Simulation↗
PubMed1995

Perfect temperature for protein structure prediction and folding.

We have investigated the influence of the "noise" of inevitable errors in energetic parameters on protein structure prediction. Because of this noise, only a part of all the interactions operating in a protein chain can be taken into account, and therefore a search for the energy minimum becomes inadequate for protein structure prediction. One can rather rely on statistical mechanics: a calculation carried out at a temperature T* somewhat below that of protein melting gives the best possible, though always approximate prediction. The early stages of protein folding also "take into account" only a part of all the interactions; consequently, the same temperature T* is favorable for the self-organization of native-like intermediates in protein folding.

Computer Simulation↗
PubMed1994

Specific nucleus as the transition state for protein folding: evidence from the lattice model.

We have studied the folding mechanism of lattice model 36-mer proteins. Using a simulated annealing procedure in sequence space, we have designed sequences to have sufficiently low energy in a given target conformation, which plays the role of the native structure in our study. The sequence design algorithm generated sequences for which the native structures is a pronounced global energy minimum. Then, designed sequences were subjected to lattice Monte Carlo simulations of folding. In each run, starting from a random coil conformation, the chain reached its native structure, which is indicative that the model proteins solve the Levinthal paradox. The folding mechanism involved nucleation growth. Formation of a specific nucleus, which is a particular pattern of contacts, is shown to be a necessary and sufficient condition for subsequent rapid folding to the native state. The nucleus represents a transition state of folding to the molten globule conformation. The search for the nucleus is a rate-limiting step of folding and corresponds to overcoming the major free energy barrier. We also observed a folding pathway that is the approach to the native state after nucleus formation; this stage takes about 1% of the simulation time. The nucleus is a spatially localized substructure of the native state having 8 out of 40 native contacts. However, monomers belonging to the nucleus are scattered along the sequence, so that several nucleus contacts are long-range while other are short-range. A folding nucleus was also found in a longer chain 80-mer, where it also constituted 20% of the native structure. The possible mechanism of folding of designed proteins, as well as the experimental implications of this study is discussed.

Algorithms↗
PubMed1993

Engineering of stable and fast-folding sequences of model proteins.

The statistical mechanics of protein folding implies that the best-folding proteins are those that have the native conformation as a pronounced energy minimum. We show that this can be obtained by proper selection of protein sequences and suggest a simple practical way to find these sequences. The statistical mechanics of these proteins with optimized native structure is discussed. These concepts are tested with a simple lattice model of a protein with full enumeration of compact conformations. Selected sequences are shown to have a native state that is very stable and kinetically accessible.

Kinetics↗
PubMed1993

A new approach to the design of stable proteins.

We propose a simple algorithm to design a sequence which fits a given protein structure with a given energy. The algorithm is a modification of the Metropolis Monte Carlo scheme in sequence space with an evolutionary temperature which sets the energy scale. There is a one to one correspondence between this optimization scheme and the Ising model of ferromagnetism. This analogy implies that the design algorithm does not encounter multiple-minima problems and is very fast. The algorithm is tested by 'predicting' the primary structures of four proteins. In each case the calculated primary structures had statistically significant homology with the natural structures.

Algorithms↗
PubMed1991

Influence of point mutations on protein structure: probability of a neutral mutation.

We investigate the probability X that a random mutation (i.e. the substitution in a random site of one amino acid residue by randomly chosen residue) will be a neutral one, i.e. it will not lead to a change in structure. Using a random energy model for the description of protein energy "levels" we show that this probability depends only on stiffness of a chain which is characterized by the number of conformations per peptide bond gamma. The result is X approximately gamma -8. The application of this result for protein engineering experiments and for possible scenario of neutral evolution is discussed.

Mathematics↗
PubMed1990

Implications of thermodynamics of protein folding for evolution of primary sequences.

Natural proteins exhibit essentially two-state thermodynamics, with one stable fold that dominates thermodynamically over a vast number of possible folds, a number that increases exponentially with the size of the protein. Here we address the question of whether this feature of proteins is a rare property selected by evolution or whether it is in fact true of a significant proportion of all possible protein sequences. Using statistical procedures developed to study spin glasses, we show that, given certain assumptions, the probability that a randomly synthesized protein chain will have a dominant fold (which is the global minimum of free energy) is a function of temperature, and that below a critical temperature the probability rapidly increases as the temperature decreases. Our results suggest that a significant proportion of all possible protein sequences could have a thermodynamically dominant fold.

Amino Acid Sequence↗