Chapter 8
Protein and Nucleic Acid
Interactions with Molecular
Dynamics Simulations
Zhen Xia and Ruhong Zhou
8.1 Introduction 218
8.2 Force Fields 219
8.3 RNA–Protein Interaction 221
8.3.1 mRNA Regulations 221
8.3.2 MicroRNA–Protein Interaction 221
8.3.3 Ribosome 223
8.3.4 Virus RNA–Protein Interaction 225
8.4 DNA–Protein Interaction 227
8.5 Integrating Experimental Data with Molecular Dynamics
Simulations 228
8.5.1 Combining Electron Microscopy and Molecular Dynamics
Simulation 229
8.5.2 Integrating Small-Angle X-Ray Scattering and Molecular
Dynamics Simulation 230
8.6 Conclusions 231
Acknowledgment 232
References 232
Protein and Nucleic Acid Interactions with Molecular Dynamics Simulations
e discovery of protein–nucleic acid interactions can be traced back to the
nineteenth century, when the association of protein–DNA strands was rst
observed by scientists with the assistance of microscopes. Since then, pro-
teins interacting with nucleic acids have been demonstrated to play a cen-
tral role in a wide range of fundamental biological processes, including gene
regulation of transcription, translation; DNA replication, repair and recom-
bination; as well as RNA processing and translocation [1,2]. During the last
decade, more than a thousand high-resolution structures of protein–nucleic
acid complexes have been determined to advance our understanding of
their biological functions and molecular mechanisms in atomistic details
(Protein Data Bank; www.pdb.org) [3].
Proteins and nucleic acids can bind in dierent ways. In general, it can be
divided into the sequence-specic binding and non-sequence-specic bind-
ing [4,5]. e nucleic acid binding regions of proteins are always located in the
conserved domains, where multiple DNA- or RNA-binding domains (DBDs or
RBDs) are found within their tertiary structures. erefore, the identity of the
individual domains and their relative arrangement are functionally impor-
tant for the protein–nucleic acid binding. Several common DBDs have been
discovered, including zinc nger [6], helix-turn-helix [7], helix-loop-helix [8],
winged helix [9], and leucine zipper [10]. RNA-binding specicity and function
are determined by the zinc nger [6], K homology [11], S1 [12], PAZ [13], PUF
[14], PIWI [15], and RNA recognition motif (RRM) domains [16–18]. e bind-
ing anity can be further increased through protein oligomerization or multi-
domain protein complex.
For certain target nucleic acid sequences, multiple nucleic acid binding
domains can increase the specicity and anity of the protein, mediate a con-
formational change in the target nucleic acid, properly position other nucleic
acid sequences for recognition, and regulate the activity of enzymatic domains
within the binding protein. In RNAs, their particular dynamic secondary
and tertiary structures are extremely important for protein recognition and
sequence-specic binding [19].
Although the details of interactions between protein and nucleic acid can
vary widely by their binding sites, the general principles remain similar by
several physical forces, such as base stacking (dispersion forces), hydrogen
bonding (dipolar interactions), salt bridges (electrostatic interactions), and
hydrophobic interactions. ese noncovalent binding forces are relatively
weak and the overall binding anity is the summation of many interactions.
Because DNA and RNA are highly charged polymers, perhaps the most obvi-
ous force is the electrostatic interactions, in which positively charged amino

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