DNA甲基化对B-Z构象转变影响的分子建模研究

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"Molecular modeling study of the effect of base methylation on internal interactions and motions in DNA and implication to B-Z conformation change* (2003年)" 是一篇自然科学领域的论文，研究了DNA碱基甲基化对其内部相互作用和热力学运动的影响，并探讨了这些变化对B-Z构象转变的潜在意义。在DNA分子中，碱基的甲基化已知能够诱导B-Z构象的转变。这篇论文利用分子力学和正常模式分析这两种强大的计算工具，深入探究特定的甲基化如何改变DNA双螺旋结构（B型和Z型）内的相互作用以及热动力学运动。通过使用Insight II分子建模软件，研究人员对比分析了C5位胞嘧啶和C8位鸟嘌呤甲基化的B型和Z型DNA双链（d(CGCGCG)2）与未甲基化的对应双链之间的内部相互作用能和熵。分子力学力场被用来计算甲基化和未甲基化的DNA双链的内部相互作用能量。这种能量计算是理解DNA稳定性及其构象变化的关键因素。正常模式分析则揭示了分子的振动模式，这些模式与分子的动态行为密切相关，包括构象转换时可能发生的结构变化。作者指出，通过比较甲基化和非甲基化的DNA，他们能够评估甲基化如何扰动碱基对间的氢键、疏水作用以及其他非共价相互作用，这些作用对于维持DNA的稳定构象至关重要。甲基化可能导致这些相互作用的强度和性质发生变化，从而影响DNA的构象。此外，论文还考虑了熵的变化，这反映了分子的无序度或自由度。在DNA的B-Z转变中，熵起着重要作用，因为构象的改变通常伴随着分子内部排列的重新组织，这将影响系统的熵值。甲基化可能会增加或减少这种熵变，从而影响构象转换的热力学可能性。论文的结论可能对理解DNA的生物学功能和表观遗传学过程具有重要意义，因为甲基化是调控基因表达和DNA稳定性的一个关键机制。通过模拟和理论分析，作者提供了关于DNA结构动态性的新见解，这些见解有助于解释甲基化如何参与DNA的复杂行为，特别是在B-Z构象转变中的作用。

Journal of Chongqing University-Eng. Ed.

Vol. 2 No. 1 June 2003

Molecular modeling study of the effect of base methylation on internal

interactions and motions in DNA and implication to B-Z conformation change

CAI Congzhong

1,2

, WANG Wanlu

CHEN Yuzong

1,2

College of Mathematics and Sciences, Chongqing University, Chongqing 400044, P. R. China

Department of Computational Science, National University of Singapore, Singapore 117543

Received 18 November 2002; revised 24 February 2003

Abstract: Methylation in the bases of DNA is known to induce B-Z conformation change. In this work, molecular mechanics and

normal mode analysis are used to probe how certain methylation affects the internal interactions and thermodynamic motions in

the DNA double helixes in both B and Z conformations, and its implication to B-Z conformation change. By molecular modeling

with Insight II, two cases involving cytosine C5 and guanine C8 methylation on both B and Z-form DNA duplex d(CGCGCG)

are

studied in comparison with the corresponding unmethylated duplexes. The internal interaction energies computed based on a

molecular mechanics force field and the entropies due to internal motions computed according to a normal mode analysis are in

fare agreement with respective observed thermodynamic quantities. The analysis on the computed individual energy terms

suggests that the observed B-Z conformation change induced by methylation is primarily driven by enthalpic factors. A

combination of changes in Van der Waals interaction, electrostatic interaction and hydrogen bonding likely contributes to the

change of enthalpy that favors Z-conformation in the methylated states.

Keywords: molecular modeling; DNA base methylation; conformation change; entropy; enthalpy

CAI Congzhong (

蔡从中

): Male; Born 1966; PhD candidate; Asst. Prof.; Research interests: bioinformatics, biophysics, material

physics and scanning probe microscope.

Funded by the International Joint Research Project of Chongqing University and National University of Singapore (ARF-151-000-014-

112), and the Basic and Applied Research Foundation of Chongqing University.

1. Introduction

Experimental studies have shown that a DNA

molecule with alternating pyrimidine-purine sequence

can adopt a left-handed, double-helical Z-DNA

conformation [1,2]. Such structural changes of DNA

occur as a consequence of environmental conditions

such as at salt concentration above 4 mol/L NaCl [1,2]

or through certain chemical modification such as

methylation [1] or bromination [2,3] of bases at

physiological conditions. These structural changes and

chemical modifications are of importance in certain

biological processes and thus are subjects of a number

of investigations [1-8].

Molecular modeling has been separately used to

construct methylated DNA structures

[4,5], to analyze

the contribution of internal interactions to the stability

of DNA duplexes

[6,7], and to examine the

contribution of internal motions to B-Z transition [8].

The success of molecular modeling in these separate

studies have raised an interesting question as to

whether it can be used to probe the mechanism of the

observed effect of methylation on DNA B-Z confor-

mation change [1,2].

In the present work, in an attempt to probe possible

mechanism of the effect of cytosine C5 and guanine C8

methylation on B-Z transition in DNA respectively,

molecular modeling techniques are used to model the

3-dimensional structures of both normal and methylated

DNAs. Effects of the methylation of every previously

mentioned bases on the internal interactions and

internal motions in both B and Z forms of DNA are

analyzed to determine how they might affect the

internal energy and other thermodynamic quantities

which are important to determination of equilibrium

state between different conformations. The results are

used to assess the effect on B-Z conformation change.

2. Methods

2.1 Structures

The structures of both B- and Z-form d(CGCGCG)

were generated from Insight II [9] in which the

standard parameters for helical rise and twist angle

were used. The structures of both B and Z forms

d(m

CGCGm

CG)

and d(CGCm

GCG)

were

generated by adding methyl groups to the relevant

positions of the corresponding B and Z form

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