In silico folding of a three helix protein and characterization of its free-energy landscape in an all-atom force field.

  title={In silico folding of a three helix protein and characterization of its free-energy landscape in an all-atom force field.},
  author={Thomas Herges and Wolfgang Wenzel},
  journal={Physical review letters},
  volume={94 1},
We report the reproducible first-principles folding of the 40 amino-acid, three-helix headpiece of the HIV accessory protein in a recently developed all-atom free-energy force field. Six of 20 simulations using an adapted basin-hopping method converged to better than 3 A backbone rms deviation to the experimental structure. Using over 60 000 low-energy conformations of this protein, we constructed a decoy tree that completely characterizes its folding funnel. 

Figures and Tables from this paper

Comparison of stochastic optimization methods for all-atom folding of the Trp-Cage protein.

The recently developed all-atom free-energy force field (PFF01) is used, which was demonstrated to correctly predict the native conformation of several proteins as the global optimum of the free energy surface.

Predictive and reproducible de novo all-atom folding of a β-hairpin loop in an improved free-energy forcefield

A greedy version of the basin-hopping technique is used with the free-energy forcefield PFF02 to reproducibly and predictively fold the structure of a β-hairpin loop.

Stochastic optimization methods for protein folding

It is demonstrated that PFF01 correctly predicts the native conformation of several proteins as the global optimum of the free energy surface.

Basin hopping simulations for all-atom protein folding.

The basin hopping technique emerges as a simple but very efficient and robust workhorse for all-atom protein folding.

A free-energy approach for all-atom protein simulation.

An effective all-atom potential for proteins

The computational efficiency of the potential makes it possible to investigate the free-energy landscape of these 49–67-residue systems with high statistical accuracy, using only modest computational resources by today's standards.

An evolutionary strategy for all-atom folding of the 60-amino-acid bacterial ribosomal protein l20.

It is argued that these structures represent a significant fraction of the low-energy metastable conformations, which characterize the folding funnel of this protein, and validate the all-atom free-energy force field PFF01 for tertiary structure prediction of a previously inaccessible structural family of proteins.

Conformational landscape of the HIV-V3 hairpin loop from all-atom free-energy simulations.

A greedy version of the basin hopping technique with the free-energy forcefield PFF02 is used to reproducibly and predictively fold the hairpin structure of a HIV-V3 loop.



Reproducible protein folding with the stochastic tunneling method.

A novel version of the stochastic tunneling method and a recently developed all-atom protein free-energy force field are used to reproduce the reproducible folding of the 20 amino-acid protein trp cage.

All-atom structure prediction and folding simulations of a stable protein.

Results are presented from all-atom, fully unrestrained ab initio folding simulations for a stable protein with nontrivial secondary structure elements and a hydrophobic core that is currently the smallest protein that displays two-state folding properties.

Solvation energy in protein folding and binding

A method for calculating the stability in water of protein structures, starting from their atomic coordinates, as the product of the accessibility of the atom to solvent and its atomic solvation parameter is developed.

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

  • A. GarciaJ. Onuchic
  • Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2003
The folding mechanism of a three-helix bundle protein is studied at atomic resolution, including effects of explicit water, and 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 ensembled are similar to those determined fromfree energy barriers.

Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution.

An implementation of classical molecular dynamics on parallel computers of increased efficiency has enabled a simulation of protein folding with explicit representation of water for 1 microsecond,

Recent improvements in prediction of protein structure by global optimization of a potential energy function

The resulting lowest-energy structures of the target proteins agreed with the experimental structures in many respects and constitute an important step toward the ab initio prediction of protein structure solely from the amino acid sequence.

Easily searched protein folding potentials.

A method for accurately recovering the given contact potential from only a knowledge of which sequences fold to which structures and what the non-native structures are and how to derive from the same information more general potential functions having much better positive correlations between potential function value and conformational deviation from the native.

Folding funnels: The key to robust protein structure prediction

The optimization procedure is outlined in the context of associative memory energy functions originally introduced for tertiary structure recognition and it is demonstrated that even partially funneled landscapes lead to qualitatively correct, low‐resolution predictions.

Theory of protein folding: the energy landscape perspective.

The energy landscape theory of protein folding suggests that the most realistic model of a protein is a minimally frustrated heteropolymer with a rugged funnel-like landscape biased toward the native structure.

The complete folding pathway of a protein from nanoseconds to microseconds

Molecular dynamics simulations give rate constants and structural details highly consistent with experiment, thereby completing the description of folding at atomic resolution.