Constructing a free energy landscape for a large molecule is difficult. One has to use either a high temperature or a strong driving force to enhance the sampling on the free energy barriers. In this work, we propose a mixed method that combines these two kinds of acceleration strategies into one simulation. First, it applies an adaptive biasing potential to some replicas of the molecule. These replicas are particularly accelerated in a collective variable space. Second, it places some unbiased and exchangeable replicas at various temperature levels. These replicas generate unbiased sampling data in the canonical ensemble. To improve the sampling efficiency, biased replicas transfer their state variables to the unbiased replicas after equilibrium by Monte Carlo trial moves. In comparison to previous integrated methods, it is more convenient for users. It does not need an initial reference biasing potential to guide the sampling of the molecule. And it is also unnecessary to insert many replicas for the requirement of passing the free energy barriers. The free energy calculation is accomplished in a single stage. It samples the data as fast as a biased simulation and it processes the data as simple as an unbiased simulation. The method provides a minimalist approach to the construction of the free energy landscape. © 2019 Wiley Periodicals, Inc.

In this paper, we calculate the absolute binding free energy of an insulin dimer by steered MD method. The result of −8.97 kcal mol−1 is close to the experimental value −7.2 kcal mol−1. We also analyze the residue–residue interactions.

Reliable conformational sampling and trajectory analysis are always important to the study of the folding or binding mechanisms of biomolecules. Generally, one has to prepare many complicated parameters and follow a lot of steps to obtain the final data. The whole process is too complicated to new users. In this article, we provide a convenient and user‐friendly tool that is compatible to AMBER, called fast sampling and analysis tool (FSATOOL). FSATOOL has some useful features. First and the most important, the whole work is extremely simplified into two steps, one is the fast sampling procedure and the other is the trajectory analysis procedure. Second, it contains several powerful sampling methods for the simulation on graphics process unit, including our previous mixing replica exchange molecular dynamics method. The method combines the advantages of the biased and unbiased simulations. Finally, it extracts the dominant transition pathways automatically from the folding network by Markov state model. Users do not need to do the tedious intermediate steps by hand. To illustrate the usage of FSATOOL in practice, we perform one simulation for a RNA hairpin in explicit solvent. All the results are presented. © 2019 Wiley Periodicals, Inc.

Molecular dynamics simulation is important in the computational study of the biomolecules. In this paper, we upgrade our previous FSATOOL to version 2.0. It is no longer a plugin as before. Besides the existed enhanced sampling and Markov state model analysis module, FSATOOL 2.0 has three new features now. First, it contains a molecular dynamics simulation engine on both CPU and GPU device. The engine works with an embedded enhanced sampling module. Second, it can do the free energy calculation by various practical methods, including the weighted histogram analysis method and Gaussian mixture model. Third, it has many subroutines to process the trajectory data, such as principal component analysis, time-structure based independent component analysis, contact analysis, and Φ-value analysis. Most importantly, all these calculations are integrated into one package. The trajectory data format is compatible with all the modules. With a proper input parameter file, users can do the molecular dynamics simulation and data analysis work by only a few simplified commands. The capabilities and theoretical backgrounds of FSATOOL 2.0 are introduced in the paper.

Complete free energy surface in the collective variable space provides important information of the reaction mechanisms of the molecules. But, sufficient sampling in the collective variable space is not easy. The space expands quickly with the number of the collective variables. To solve the problem, many methods utilize artificial biasing potentials to flatten out the original free energy surface of the molecule in the simulation. Their performances are sensitive to the definitions of the biasing potentials. Fast-growing biasing potential accelerates the sampling speed but decreases the accuracy of the free energy result. Slow-growing biasing potential gives an optimized result but needs more simulation time. In this article, we propose an alternative method. It adds the biasing potential to a representative point of the molecule in the collective variable space to improve the conformational sampling. And the free energy surface is calculated from the free energy gradient in the constrained simulation, not given by the negative of the biasing potential as previous methods. So the presented method does not require the biasing potential to remove all the barriers and basins on the free energy surface exactly. Practical applications show that the method in this work is able to produce the accurate free energy surfaces for different molecules in a short time period. The free energy errors are small in the cases of various biasing potentials. © 2017 Wiley Periodicals, Inc.