Dmitrii E Makarov

Learn More
Most small, single-domain proteins fold with the uncomplicated, single-exponential kinetics expected for diffusion on a smooth energy landscape. Despite this energetic smoothness, the folding rates of these two-state proteins span a remarkable million-fold range. Here, we review the evidence in favor of a simple, mechanistic description, the topomer search(More)
Experiments have shown that the folding rate constants of two dozen structurally unrelated, small, single-domain proteins can be expressed in terms of one quantity (the contact order) that depends exclusively on the topology of the folded state. Such dependence is unique in chemical kinetics. Here we investigate its physical origin and derive the(More)
We consider the mechanical stretching of a polypeptide chain formed by multiple interacting repeats. The folding thermodynamics and the interactions among the repeats are described by the Ising model. Unfolded repeats act as soft entropic springs, whereas folded repeats respond to a force as stiffer springs. We show that the resulting force-extension curve(More)
Internal friction, which reflects the "roughness" of the energy landscape, plays an important role for proteins by modulating the dynamics of their folding and other conformational changes. However, the experimental quantification of internal friction and its contribution to folding dynamics has remained challenging. Here we use the combination of(More)
Do highly denatured proteins adopt random coil configurations? Here, we address this question by measuring residue-to-residue separations across the denatured FynSH3 domain. Using single-molecule Forster resonance energy transfer techniques, we have collected transfer efficiency probability distributions for dye-labeled, denatured protein. Applying maximum(More)
Recently, it has become possible to unfold a single protein molecule titin, by pulling it with an atomic-force-microscope tip. In this paper, we propose and study a stochastic kinetic model of this unfolding process. Our model assumes that each immunoglobulin domain of titin is held together by six hydrogen bonds. The external force pulls on these bonds and(More)
In recent years, elastic network models (ENM) have been widely used to describe low-frequency collective motions in proteins. These models are often validated and calibrated by fitting mean-square atomic displacements estimated from x-ray crystallography (B-factors). We show that a proper calibration procedure must account for the rigid-body motion and(More)
Single-molecule experiments in which proteins are unfolded by applying mechanical stretching forces generally force unfolding to proceed along a reaction coordinate that is different from that in chemical or thermal denaturation. Here we simulate the mechanical unfolding and refolding of a minimalist off-lattice model of the protein ubiquitin to explore in(More)
A method to denoise single-molecule fluorescence resonance energy (smFRET) trajectories using wavelet detail thresholding and Bayesian inference is presented. Bayesian methods are developed to identify fluorophore photoblinks in the time trajectories. Simulated data are used to quantify the improvement in static and dynamic data analysis. Application of the(More)
Single-molecule studies in which a mechanical force is transmitted to the molecule of interest and the molecular extension or position is monitored as a function of time are versatile tools for probing the dynamics of protein folding, stepping of molecular motors, and other biomolecular processes involving activated barrier crossing. One complication in(More)