Parallel tempering simulations of HP‐36

Abstract

We report results from all-atom Monte Carlo simulations of the 36-residue villin headpiece subdomain HP-36. Protein-solvent interactions are approximated by an implicit solvent model. The parallel tempering is used to overcome the problem of slow convergence in low-temperature protein simulations. Our results show that this technique allows one to sample native-like structures of small proteins and points out the need for improved energy functions.

In SilicoFolding of a Three Helix Protein and Characterization of Its Free-Energy Landscape in an All-Atom Force Field

“…The development of such techniques, in particular of transferable first-principle all-atom folding methods, would significantly benefit the understanding of protein families where little experimental information is available, the prediction of novel folds as well as the investigation of protein association and dynamics which are presently difficult to probe experimentally. Recent progress for small peptides [3,6,7,8] documents both the feasibility of this approach as well as its limitations [9,10], in particualr those associated with the direct simulation of the folding process through molecular dynamics [11].Overwhelming experimental evidence supports the thermodynamic hypothesis [12] that many proteins are in thermodynamic equilibrium with their environment: their native state thus corresponds to the global minimum of their free energy landscape [13]. The free energy of the system is accessible either indirectly by explicit ensemble averaging of the combined internal energy of protein and solvent, or directly in a free-energy forcefield where an implicit solvation model approximates direct interactions with the solvent as well as most of the entropic contributions.…”

“…We developed an all-atom protein forcefield (PFF01) [8,14,15] with an area-based implicit solvent model that approximates the free energy of peptide conformations in the natural solvent. Using a rational decoy approach this forcefield was optimized to correctly predict the native structure of the 36-amino acid headgroup of villin [9,10,11]. Without further parameter adjustment we then simulated the structurally conserved 40 amino-acid headpiece of the autonomously folding HIV accessory protein (1F4I-40) [16] with a modified basin hopping technique [17,18].…”

“…The development of such techniques, in particular of transferable first-principle all-atom folding methods, would significantly benefit the understanding of protein families where little experimental information is available, the prediction of novel folds as well as the investigation of protein association and dynamics which are presently difficult to probe experimentally. Recent progress for small peptides [3,6,7,8] documents both the feasibility of this approach as well as its limitations [9,10], in particualr those associated with the direct simulation of the folding process through molecular dynamics [11].…”

Secondary structure prediction of beta-hairpin peptide tryptophan zipper-I

“…Thermal unfolding temperature of trpzip-I molecule was determined as 323 K experimentally [11]. The relatively low transition temperature that was obtained may be attributed to well-known force field uncertainties [35].…”

Protein structure prediction by tempering spatial constraints

“…Such simulations require the use of a suitable model that describes sufficiently accurate the interactions within a protein and with its environment (most noticeable the surrounding water molecules). Unfortunately, current energy functions do not always distinguish between native-like conformations and other low-energy conformers [1], and their use in structure prediction calculations is therefore limited.…”