arXiv subjects

Eugene Shakhnovich

Publications and source records attributed to Eugene Shakhnovich.

24 records · Page 2Linked to original sources

arXiv2004

Simulation, Experiment, and Evolution: Understanding Nucleation in Protein S6 Folding

In this study, we explore nucleation and the transition state ensemble of the ribosomal protein S6 using a Monte Carlo Go model in conjunction with restraints from experiment. The results are analyzed in the context of extensive experimental and evolutionary data. The roles of individual residues in the folding nucleus are identified and the order of events in the S6 folding mechanism is explored in detail. Interpretation of our results agrees with, and extends the utility of, experiments that shift f-values by modulating denaturant concentration and presents strong evidence for the realism of the mechanistic details in our Monte Carlo Go model and the structural interpretation of experimental f-values. We also observe plasticity in the contacts of the hydrophobic core that support the specific nucleus. For S6, which binds to RNA and protein after folding, this plasticity may result from the conformational flexibility required to achieve biological function. These results present a theoretical and conceptual picture that is relevant in understanding the mechanism of nucleation in protein folding.

q-bio.BM↗

arXiv2003

Solvation vs. freezing in a heteropolymer globule

We address the response of a random heteropolymer to preferential solvation of certain monomer types at the globule-solvent interface. For each set of monomers that can comprise the molecule's surface, we represent the ensemble of allowed configurations by a Gaussian distribution of energy levels, whose mean and variance depend on the set's composition. Within such a random energy model, mean surface composition is proportional to solvation strength under most conditions. The breadth of this linear response regime arises from approximate statistical independence of surface and volume energies. For a diverse set of monomer types, the excess of solvophilic monomers at the surface is large only for very strong solvent preference, even in the ground state.

cond-mat.soft↗

arXiv2000

Evolutionary conservation of the folding nucleus

In this Communication we present statistical analysis of conservation profiles in families of homologous sequences for nine proteins whose folding nucleus was determined by protein engineering methods. We show that in all but one protein (AcP) folding nucleus residues are significantly more conserved than the rest of the protein. Two aspects of our study are especially important: 1) grouping of amino acids into classes according to their physical-chemical properties and 2) proper normalization of amino acid probabilities that reflects the fact that evolutionary pressure to conserve some amino acid types may itself affect concentration of various amino acid types in protein families. Neglect of any of those two factors may make physical and biological ``signals'' from conservation profiles disappear.

physics.bio-ph↗

arXiv2000

Dynamic charge density correlation function in weakly charged polyampholyte globules

We study solutions of statistically neutral polyampholyte chains containing a large fraction of neutral monomers. It is known that, even if the quality of the solvent with respect to the neutral monomers is good, a long chain will collapse into a globule. For weakly charged chains, the interior of this globule is semi-dilute. This paper considers mainly theta-solvents, and we calculate the dynamic charge density correlation function g(k,t) in the interior of the globules, using the quadratic approximation to the Martin-Siggia-Rose generating functional. It is convenient to express the results in terms of dimensionless space and time variables. Let R be the blob size, and let T be the characteristic time scale at the blob level. Define the dimensionless wave vector q = R k, and the dimensionless time s = t/T. We find that for q<1, corresponding to length scales larger than the blob size, the charge density fluctuations relax according to g(q,s) = q^2(1-s^(1/2)) at short times s < 1, and according to g(q,s) = q^2 s^(-1/2) at intermediate times 1 < s < q^(-4). We expect these results to be valid for wave vectors q > 0.1, where entanglements are unimportant.

cond-mat↗

arXiv1999

Freezing in polyampholyte globules: Influence of the long-range nature of the interaction

In random heteropolymer globules with short-range interactions between the monomers, freezing takes place at the microscopic length scale only, and can be described by a 1-step replica symmetry breaking. The fact that the long-range Coulomb interaction has no intrinsic length scale suggests that freezing in random polyampholyte globules might take place at all length scales, corresponding to an overlap parameter q(x) that increases continuously from zero to its maximum value. Study of the polyampholyte globule within the independent interaction approximation seems to confirm this scenario. However, the independent interaction model has an important deficiency: it cannot account for self-screening, and we show that the model is only reliable at length scales shorter than the self-screening length. Using the more realistic sequence model we prove that in the general case of a random heteropolymer globule containing two types of monomers such that unlike monomers attract each other, freezing at arbitrarily large length scales is not possible. For polyampholyte globules this implies that beyond the self-screening length, the freezing behavior is qualitatively the same as in the case of short-range interactions. We find that if the polyampholyte globule is not maximally compact, the degree of frustration is insufficient to obtain freezing.

cond-mat.soft↗

arXiv1998

Factors that Affect the Folding Ability of Proteins

The folding ability of a heteropolymer model for proteins subject to Monte Carlo dynamics on a simple cubic lattice is shown to be strongly correlated with the energy gap between the native state and the structurally dissimilar part of the spectrum. We consider a number of estimates of the energy gap that can be determined without simulation, including the gap in energy between the native and first excited fully compact states for sequences with fully compact native states. These estimates are found to be more robust predictors of folding ability than a parameter $σ$ that requires simulation for its evaluation: $σ= 1 - T_f/T_θ$, where $T_f$ is the temperature at which the fluctuation of the order parameter is at its maximum and $T_θ$ is the temperature at which the specific heat is at its maximum. We show that the interpretation of $T_θ$ as the collapse transition temperature is not correct in general and that the correlation between $σ$ and the folding ability arises from the fact that $σ$ is essentially a measure of the energy gap.

cond-mat↗