Abstract
We propose a protocol that provides a systematic definition of reaction coordinate and related free-energy profile as the function of temperature for the protein-folding simulation. First, using action-derived molecular dynamics (ADMD), we investigate the dynamic folding pathway model of a protein between a fixed extended conformation and a compact conformation. We choose the pathway model to be the reaction coordinate, and the folding and unfolding processes are characterized by the ADMD step index, in contrast to the common a priori reaction coordinate as used in conventional studies. Second, we calculate free-energy profile as the function of temperature, by employing the replica-exchange molecular dynamics (REMD) method. The current method provides efficient exploration of conformational space and proper characterization of protein folding/unfolding dynamics from/to an arbitrary extended conformation. We demonstrate that combination of the two simulation methods, ADMD and REMD, provides understanding on molecular conformational changes in proteins. The protocol is tested on a small protein, penta-peptide of met-enkephalin. For the neuropeptide met-enkephalin system, folded, extended, and intermediate sates are well-defined through the free-energy profile over the reaction coordinate. Results are consistent with those in the literature.
Highlights
Understanding the protein folding process inside a living cell is one of the most important issues in modern biology [1,2], and an accurate description of the protein folding pathway has remained a challenging problem in molecular biology for the last few decades
Computational approaches based on the energy function of a protein conformation have provided valuable knowledge about the protein folding mechanism along with various experimental techniques such as kinetics study with circular dichroism measurement, NMR spectroscopy, X-ray crystallography, and/or Fersht Φ value analysis [3,4,5]
By studying the free-energy profile along the action-derived molecular dynamics (ADMD) folding pathway, we find that there exists an ensemble of populated structures along the pathway
Summary
Understanding the protein folding process inside a living cell is one of the most important issues in modern biology [1,2], and an accurate description of the protein folding pathway has remained a challenging problem in molecular biology for the last few decades. They found that during barrier crossing, the long-range contacts that establish the protein’s overall fold form early along with the formation of a considerable amount of secondary structures and surface burial Another difficulty is that, in general, it is difficult to define a good reaction coordinate for description of protein folding/unfolding dynamics from/to an arbitrary extended conformation [8]. The first algorithm we use is the action-derived molecular dynamics (ADMD) method [9,10], and it is used to generate protein folding pathways. We propose a methodology to construct free-energy profile along the folding pathway of a protein by combining ADMD and REMD methods.
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