All-atom Molecular Simulations On DNA Flexibility Based On Amber Bsc1 And Bsc0 Force Fields

The structural flexibility of DNA plays a key role in many biological processes of DNA,such as protein-DNA interactions,DNA packaging in viruses and nucleosome positioning on genomic DNA.Some experimental techniques have been employed to investigate the structural flexibility of DNA with the combination of elastic models,but these experiments could only provide the macroscopic properties of DNA,and thus,it was still difficult to understand the corresponding microscopic mechanisms.Recently,all-atom molecular dynamics(MD)simulation has emerged as a useful tool to investigate not only the macroscopic properties of DNA,but also the microscopic description of the flexibility of DNA at the atomic level.The most important issue in all-atom MD simulations of DNA is to choose an appropriate force field for simulating DNA.Very recently,a new force field for DNA has been developed based on the last generation force field of Amber bscO,which was named as Amber bscl.In this work,all-atom MD simulations were employed to study the flexibility of a 30-bp DNA with the force fields of Amber bsc1 and Amber bscO in a comparative way.Our aim of the research was to examine the improvement of the new development of force field(Amber bsc1)on the macroscopic and microscopic properties of DNA,in comparison with the corresponding experimental measurements.All the MD simulations were performed with Gromacs 4.6 and lasted with a simulation time of 600 ns.The MD trajectories were analyzed with Curves+ for the last 500 ns,since the systems reached equilibrium approximately after-100 ns.Our results show that the new force field(Amber bsc1)can lead to the improvements on the macroscopic parameters of DNA flexibility,i.e.,stretch modulus S and twist-stretch coupling D become closer to experimental measurements,while bending persistence lengths lp and torsional persistence lengths C from the two force fields(bscl and bscO)are both in good agreement with experimental data.Our microscopic analyses show that the microscopic structure parameters of DNA from the MD simulation with the Amber bsc 1 force field are closer to the experimental values than those with the Amber bscO force field,except for slide,and the obvious improvements have been observed in some microscopic parameters such as twist and inclination.Our further analyses show that the improvements on macroscopic flexibility from the Amber bscl force field are tightly related to the microscopic parameters and their fluctuations,the structure and flexibility of DNA has sequence dependence.Many previous studies have shown that base sequence could significantly influence the structure and dynamics of DNA,and the stability of DNA can be evaluated by the nearest-neighbor free energy parameters of base steps.To explore the possible correlation between flexibility and stability of DNA,we used all-atom MD simulations based on Amber bscl force field to study the flexibility of nine 30-bp DNAs with different sequences.We calculated the macroscopic elastic parameters of the nine DNAs including bending persistence length lp,stretching modulus S and torsional persistence length C,to find the possible coupling between these macroscopic elastic parameters and the corresponding stability of DNA.Our calculations show that,there is apparent coupling between the flexibility in bending and stretching and the stability for DNAs,while there is no obvious correlation between torsional flexibility and stability.Through the microscopic analyses,we found the bending flexibility of DNA may be related to the width and fluctuation of major groove,since DNA generally bend towards major groove to achieve large bending.With the increase of the formation free energy of DNA,the width and fluctuation of major groove become larger and correspondingly the bending persistence length of DNA becomes smaller.Our microscopic analyses for different DNA sequences indicate that the stronger stretching flexibility of DNA is attributed to the larger slide and inclination fluctuation.Finally,our analyses show that the fluctuation of twist is not sensitive to the change of free energy of DNA formation,indicating that there is no obvious coupling between the torsional flexibility and stability of DNA.