A fast tomographic method for searching the minimum free energy path

Chen, Changjun; Huang, Yanzhao; Jiang, Xuewei; Xiao, Yi

doi:10.1063/1.4897983

Cited by 12 publications

(19 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This method shows promise to be used extensively over a range of protein-DNA and drug-DNA complexes with HG base pairing, and make comparison between ∆G WC→HG free energies possible within reasonable computing time. Pathways and timescales of HG pairing in such systems can be understood from Markov state models and multidimensional path searching methods like TPSS (72), String methods (73)(74)(75) and other similar techniques (76,77). Taking additional degrees of freedom like H-bond donor-acceptor distances, sugar pucker angles, and phopho-diester bond torsion angle into consideration, will provide better understanding of the molecular processes involved in HG base pair formation.…”

Section: Resultsmentioning

confidence: 99%

Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA

Ray

Andricioaei

2020

Preprint

View full text Add to dashboard Cite

Genetic information is encoded in the DNA double helix which, in its physiological milieu, is characterized by the iconical Watson-Crick nucleobase pairing. Recent NMR relaxation experiments revealed the transient presence of an alternative, Hoogsteen base pairing pattern in naked DNA duplexes and estimated its relative stability and lifetime. In contrast, HG transitions in RNA were not observed. Understanding Hoogsteen (HG) base pairing is important because the underlying "breathing" can modulate significantly DNA/RNA recognition by proteins. However, a detailed mechanistic insight into the transition pathways and kinetics is still missing. We performed enhanced sampling simulation (with combined metadynamics and adaptive force bias method) and Markov State modeling to obtain accurate free energy, kinetics and the intermediates in the transition pathway between WC and HG base pair for both naked B-DNA and A-RNA duplexes. The Markov state model constructed from our unbiased MD simulation data revealed previously unknown complex extra-helical intermediates in this seemingly simple process of base pair conformation switching in B-DNA. Extending our calculation to A-RNA, for which HG base pair is not observed experimentally, resulted in relatively unstable single hydrogen bonded distorted Hoogsteen like base pair. Unlike B-DNA the transition pathway primarily involved base paired and intra-helical intermediates with transition timescales much higher than that of B-DNA. The seemingly obvious flip-over reaction coordinate, i.e., the glycosidic torsion angle is unable to resolve the intermediates; so a multidimensional picture, involving backbone dihedral angles and distance between atoms participating in hydrogen bonds, is required to gain insight into the molecular mechanism. SIGNIFICANCE Formation of unconventional Hoogsteen (HG) base pairing is an important problem in DNA biophysics owing to its key role in facilitating the binding of DNA repairing enzymes, proteins and drugs to damaged DNA. X-ray crystallography and NMR relaxation experiments revealed the presence of HG base pair in naked DNA duplex and protein-DNA complex but no HG base pair was observed in RNA. Molecular dynamics simulations could reproduce the experimental free energy cost of HG base pairing in DNA although a detailed mechanistic insight is still missing. We performed enhanced sampling simulation and Markov state modeling to obtain accurate free energy, kinetics and the intermediates in the transition pathway between WC and HG base pair for both B-DNA and A-RNA.Manuscript submitted to Biophysical Journal 1 D. Ray and I. Andricioaei duplex DNA beyond what can be achieved by Watson-Crick base-pairing alone. For example, HG base pairs are recognized by DNA repairing enzymes resulting in selective binding in the damaged regions of DNA, rich in syn-anti configuration over the anti-anti WC base pair rich normal DNA. Thus, apart from providing structural integrity to the damaged and deformed DNA, HG base pairs assist in the DNA repair mechanism (13).A...

show abstract

Section: Resultsmentioning

confidence: 99%

Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA

Ray

Andricioaei

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…To reduce the movement distance, the control parameter s step must be smaller than 1.0. The second operation is to smooth the updated path at every iteration by a positive objective function [30]. χ ( i -1) , χ ( i ) and χ ( i +1) are the positions of the i -1th, i th and i +1th snapshot.…”

Section: Resultsmentioning

confidence: 99%

“…After a few iterations, the method finally optimizes the initial path to the most probable transition path [28]. Besides, path metadynamics [29] and tomographic method [30, 31] update the path in a more direct way. They calculate the average positions of the snapshots (as in path metadynamics [29]) or the free energy minima (as in tomographic method [30, 31]) on the perpendicular hyperplanes by different strategies and move the snapshots towards the targets subsequently.…”

Section: Introductionmentioning

confidence: 99%

Fast exploration of an optimal path on the multidimensional free energy surface

Chen

2017

PLoS ONE

Self Cite

View full text Add to dashboard Cite

In a reaction, determination of an optimal path with a high reaction rate (or a low free energy barrier) is important for the study of the reaction mechanism. This is a complicated problem that involves lots of degrees of freedom. For simple models, one can build an initial path in the collective variable space by the interpolation method first and then update the whole path constantly in the optimization. However, such interpolation method could be risky in the high dimensional space for large molecules. On the path, steric clashes between neighboring atoms could cause extremely high energy barriers and thus fail the optimization. Moreover, performing simulations for all the snapshots on the path is also time-consuming. In this paper, we build and optimize the path by a growing method on the free energy surface. The method grows a path from the reactant and extends its length in the collective variable space step by step. The growing direction is determined by both the free energy gradient at the end of the path and the direction vector pointing at the product. With fewer snapshots on the path, this strategy can let the path avoid the high energy states in the growing process and save the precious simulation time at each iteration step. Applications show that the presented method is efficient enough to produce optimal paths on either the two-dimensional or the twelve-dimensional free energy surfaces of different small molecules.

show abstract

“…Beside the heat capacity, the other parameter that can show the reliability of the method is the free energy. Correct free energies of the critical states of the molecule represent the stabilities of states and determine the directions of the reactions . Finding more and more minima on the free energy surface and calculating their free energies in a finite time period has always been the important target of the simulation.…”

Section: Resultsmentioning

confidence: 99%

Walking freely in the energy and temperature space by the modified replica exchange molecular dynamics method

Chen

Huang

2016

J. Comput. Chem.

Self Cite

View full text Add to dashboard Cite

Replica Exchange Molecular Dynamics (REMD) method is a powerful sampling tool in molecular simulations. Recently, we made a modification to the standard REMD method. It places some inactive replicas at different temperatures as well as the active replicas. The method completely decouples the number of the active replicas and the number of the temperature levels. In this article, we make a further modification to our previous method. It uses the inactive replicas in a different way. The inactive replicas first sample in their own knowledge-based energy databases and then participate in the replica exchange operations in the REMD simulation. In fact, this method is a hybrid between the standard REMD method and the simulated tempering method. Using different active replicas, one can freely control the calculation quantity and the convergence speed of the simulation. To illustrate the performance of the method, we apply it to some small models. The distribution functions of the replicas in the energy space and temperature space show that the modified REMD method in this work can let the replicas walk freely in both of the two spaces. With the same number of the active replicas, the free energy surface in the simulation converges faster than the standard REMD. © 2016 Wiley Periodicals, Inc.

show abstract

A fast tomographic method for searching the minimum free energy path

Cited by 12 publications

References 43 publications

Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA

Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA

Fast exploration of an optimal path on the multidimensional free energy surface

Walking freely in the energy and temperature space by the modified replica exchange molecular dynamics method

Contact Info

Product

Resources

About