The computational study of conformational transitions in RNA and proteins with atomistic molecular dynamics often requires suitable enhanced sampling techniques. We here introduce a novel method where concurrent metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strength of the bias potential exploiting the tunability of well-tempered metadynamics. Using this method, free-energy barriers of individual collective variables are significantly reduced compared with simple force-field scaling. The introduced methodology is flexible and allows adaptive bias potentials to be self-consistently constructed for a large number of simple collective variables, such as distances and dihedral angles. The method is tested on alanine dipeptide and applied to the difficult problem of conformational sampling in a tetranucleotide.
Methods that combine collective variable (CV) based enhanced sampling and global tempering approaches are used in speeding-up the conformational sampling and free energy calculation of large and soft systems with a plethora of energy minima. In this paper, a new method of this kind is proposed in which the well-sliced metadynamics approach (WSMTD) is united with Replica Exchange with Solute Tempering (REST2) method. WSMTD employs a divide-and-conquer strategy wherein high-dimensional slices of a free energy surface are independently sampled and combined. The method enables one to accomplish a …
Parallel tempering Monte Carlo has proven to be an efficient method in optimization and sampling applications. Having an optimized temperature set enhances the efficiency of the algorithm through more-frequent replica visits to the temperature limits. The approaches for finding an optimal temperature set can be divided into two main categories. The methods of the first category distribute the replicas such that the swapping ratio between neighbouring replicas is constant and independent of the temperature values. The second-category techniques including the feedback-optimized method, on the ot…
We combine replica exchange (parallel tempering) with normalizing flows, a class of deep generative models. These two sampling strategies complement each other, resulting in an efficient strategy for sampling molecular systems characterized by rare events, which we call learned replica exchange (LREX). In LREX, a normalizing flow is trained to map the configurations of the fastest-mixing replica into configurations belonging to the target distribution, allowing direct exchanges between the two without the need to simulate intermediate replicas. This can significantly reduce the computational c…
A Second Look at Canonical Sampling of Biomolecules using Replica Exchange Simulation
由于对基于温度的采样方法（如副本交换）的兴趣越来越大，本文旨在进行一些观察，并提出一些我们在文献中尚未充分解决的潜在重要问题。主要是，我们希望提请注意的限制，最大的速度从温度为基础的方法预期，也注意到需要仔细量化的采样效率。由于可能需要进行长期研究来解决这些问题，我们认为将其提请更广泛的社会关注是有益的。这里对\emph{we are strictly concerned with canonical sampling at a fixed temperature,}和\emph{not}进行构象搜索。
In replica exchange Monte Carlo (REM), tuning of the temperature set and the exchange scheduling are crucial in improving the accuracy and reducing calculation time. In multi-dimensional simulated tempering, the first order phase transition is accessible. Therefore it is important to study the tuning of parameter set and the scheduling of exchanges in the parallel counterpart, the multi-dimensional REM. We extend Hukushima's constant exchange probability method to multi-dimensional REM for the parameter set. We further propose a combined method to use this set and the Bittner-Nussbaumer-Janke'…
The computational study of conformational transitions in nucleic acids still faces many challenges. For example, in the case of single stranded RNA tetranucleotides, agreement between simulations and experiments is not satisfactory due to inaccuracies in the force fields commonly used in molecular dynamics simulations. We here use experimental data collected from high-resolution X-ray structures to attempt an improvement of the latest version of the AMBER force field. A modified metadynamics algorithm is used to calculate correcting potentials designed to enforce experimental distributions of …
RNA function is intimately related to its structural dynamics. Molecular dynamics simulations are useful for exploring biomolecular flexibility but are severely limited by the accessible timescale. Enhanced sampling methods allow this timescale to be effectively extended in order to probe biologically-relevant conformational changes and chemical reactions. Here, we review the role of enhanced sampling techniques in the study of RNA systems. We discuss the challenges and promises associated with the application of these methods to force-field validation, exploration of conformational landscapes…
讨论了作为稀有事件抽样方法的多正则MCMC（Multicanonical Markov Chain Monte Carlo; Multicanonical Monte Carlo）。从审查的一般框架的重要性抽样，多规范MCMC介绍，其次是随机矩阵，随机图，混沌动力系统中的应用。双交换MCMC（也称为并行回火或Metropolis耦合MCMC）也被解释为多规范MCMC的替代方案。在最后一节中，多规范MCMC被应用到数据代理，一个成功的实现在代理时间序列。在附录中，计算的平均值和归一化常数在一个指数的家庭，相共存，模拟回火，并行化，和多元扩展进行了讨论。
The sampling problem lies at the heart of atomistic simulations and over the years many different enhanced sampling methods have been suggested towards its solution. These methods are often grouped into two broad families. On the one hand methods such as umbrella sampling and metadynamics that build a bias potential based on few order parameters or collective variables. On the other hand, tempering methods such as replica exchange that combine different thermodynamic ensembles in one single expanded ensemble. We instead adopt a unifying perspective, focusing on the target probability distribut…
