Protein folding simulations: From coarse‐grained model to all‐atom model

Abstract

SummaryProtein folding is an important and challenging problem in molecular biology. During the last two decades, molecular dynamics (MD) simulation has proved to be a paramount tool and was widely used to study protein structures, folding kinetics and thermodynamics, and structure-stability-function relationship. It was also used to help engineering and designing new proteins, and to answer even more general questions such as the minimal number of amino acid or the evolution principle of protein families. Nowadays, the MD simulation is still undergoing rapid developments. The first trend is to toward developing new coarse-grained models and studying larger and more complex molecular systems such as protein-protein complex and their assembling process, amyloid related aggregations, and structure and motion of chaperons, motors, channels and virus capsides; the second trend is toward building high resolution models and explore more detailed and accurate pictures of protein folding and the associated processes, such as the coordination bond or disulfide bond involved folding, the polarization, charge transfer and protonate/deprotonate process involved in metal coupled folding, and the ion permeation and its coupling with the kinetics of channels. On these new territories, MD simulations have given many promising results and will continue to offer exciting views. Here, we review several new subjects investigated by using MD simulations as well as the corresponding developments of appropriate protein models. These include but are not limited to the attempt to go beyond the topology based Gō-like model and characterize the energetic factors in protein structures and dynamics, the study of the thermodynamics and kinetics of disulfide bond involved protein folding, the modeling of the interactions between chaperonin and the encapsulated protein and the protein folding under this circumstance, the effort to clarify the important yet still elusive folding mechanism of protein BBL, the development of discrete MD and its application in studying the a-b conformational conversion and oligomer assembling process, and the modeling of metal ion involved protein folding.

Transition paths, diffusive processes, and preequilibria of protein folding

“…With the advent of site-directed mutagenesis, the concept of free energy barriers from transition state theory (TST) (3) was introduced to interpret mutational data (4), and subsequently, it was adopted for the Φ-value analysis (5). Since the 1990s, the availability of more detailed experimental data (6), in conjunction with computational development of coarse-grained chain models, has led to an energy landscape picture of folding (7)(8)(9)(10)(11)(12)(13)(14)(15). This perspective emphasizes the diversity of microscopic folding trajectories, and it conceptualizes folding as a diffusive process (16)(17)(18)(19)(20)(21)(22)(23)(24)(25) akin to the theory of Kramers (26).…”

As Simple As Possible, but Not Simpler: Exploring the Fidelity of Coarse-Grained Protein Models for Simulated Force Spectroscopy

“…In this regard, minimal models have enjoyed success in testing, refining, and validating the conceptual foundations of the energy landscape theory of protein folding [3–7] as well as forced unfolding mechanisms [8]. A minimal model attempts to capture the essential dynamical behavior of a protein, while upholding the notion of simplicity along with its concommitant computational efficiency.…”

Modified Off-lattice AB Model for Protein Folding Problem Using the Vortex Search Algorithm

“…Perhaps the most widely studied model is the so called HP model [2], in which each amino-acid in a protein chain is considered either hydrophobic or polar. In the HP model, high resolution lattice models are used to accurately model the protein structure and to retain the computational efficiency of lattice models as well [3]. In lattice models, each amino-acid is mapped to a particular lattice point to form a continuous and self-avoiding amino-acid chain with fix bond lengths between successive amino-acid pairs.…”

“…The lattice models benefits greatly from the discretization of protein phase space; however, it also suffers from this strategy. The discrete nature of the model surely affects the folding behaviors, especially the dynamics of the system [3]. To overcome this problem off-lattice model (or toy model) was proposed [4].…”