Dataset Information

Folding a protein in a computer: an atomic description of the folding/unfolding of protein A.

ABSTRACT: We study the folding mechanism of a three-helix bundle protein at atomic resolution, including effects of explicit water. Using replica exchange molecular dynamics we perform enough sampling over a wide range of temperatures to obtain the free energy, entropy, and enthalpy surfaces as a function of structural reaction coordinates. Simulations were started from different configurations covering the folded and unfolded states. Because many transitions between all minima at the free energy surface are observed, a quantitative determination of the free energy barriers and the ensemble of configurations associated with them is now possible. The kinetic bottlenecks for folding can be determined from the thermal ensembles of structures on the free energy barriers, provided the kinetically determined transition-state ensembles are similar to those determined from free energy barriers. A mechanism incorporating the interplay among backbone ordering, sidechain packing, and desolvation arises from these calculations. Large Phi values arise not only from native contacts, which mostly form at the transition state, but also from contacts already present in the unfolded state that are partially destroyed at the transition.

SUBMITTER: Garcia AE

PROVIDER: S-EPMC283518 | biostudies-literature | 2003 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Folding a protein in a computer: an atomic description of the folding/unfolding of protein A.

García Angel E AE Onuchic José N JN

Proceedings of the National Academy of Sciences of the United States of America 20031117 24

We study the folding mechanism of a three-helix bundle protein at atomic resolution, including effects of explicit water. Using replica exchange molecular dynamics we perform enough sampling over a wide range of temperatures to obtain the free energy, entropy, and enthalpy surfaces as a function of structural reaction coordinates. Simulations were started from different configurations covering the folded and unfolded states. Because many transitions between all minima at the free energy surface ...[more]

PMID: 14623983

Similar Datasets

Project description:Cardiac myosin-binding protein-C (cMyBP-C) is a thick-filament-associated protein that performs regulatory and structural roles within cardiac sarcomeres. It is a member of the immunoglobulin (Ig) superfamily of proteins consisting of eight Ig- and three fibronectin (FNIII)-like domains, along with a unique regulatory sequence referred to as the M-domain, whose structure is unknown. Domains near the C-terminus of cMyBP-C bind tightly to myosin and mediate the association of cMyBP-C with thick (myosin-containing) filaments, whereas N-terminal domains, including the regulatory M-domain, bind reversibly to myosin S2 and/or actin. The ability of MyBP-C to bind to both myosin and actin raises the possibility that cMyBP-C cross-links myosin molecules within the thick filament and/or cross-links myosin and thin (actin-containing) filaments together. In either scenario, cMyBP-C could be under mechanical strain. However, the physical properties of cMyBP-C and its behavior under load are completely unknown. Here, we investigated the mechanical properties of recombinant baculovirus-expressed cMyBP-C using atomic force microscopy to assess the stability of individual cMyBP-C molecules in response to stretch. Force-extension curves showed the presence of long extensible segment(s) that became stretched before the unfolding of individual Ig and FNIII domains, which were evident as sawtooth peaks in force spectra. The forces required to unfold the Ig/FNIII domains at a stretch rate of 500 nm/s increased monotonically from ∼30 to ∼150 pN, suggesting a mechanical hierarchy among the different Ig/FNIII domains. Additional experiments using smaller recombinant proteins showed that the regulatory M-domain lacks significant secondary or tertiary structure and is likely an intrinsically disordered region of cMyBP-C. Together, these data indicate that cMyBP-C exhibits complex mechanical behavior under load and contains multiple domains with distinct mechanical properties.

Dataset Information

Folding a protein in a computer: an atomic description of the folding/unfolding of protein A.

Publications

Folding a protein in a computer: an atomic description of the folding/unfolding of protein A.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets