Research Article Structural, Dynamical, and Energetical Consequences of Rett Syndrome Mutation R133C in MeCP2 Tugba G. Kucukkal and Emil Alexov Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA Correspondence should be addressed to Tugba G. Kucukkal; tugbak@g.clemson.edu Received 15 December 2014; Accepted 11 March 2015 Academic Editor: Volkhard Helms Copyright © 2015 T. G. Kucukkal and E. Alexov. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rett Syndrome (RTT) is a progressive neurodevelopmental disease afecting females. RTT is caused by mutations in the MECP2 gene and various amino acid substitutions have been identifed clinically in diferent domains of the multifunctional MeCP2 protein encoded by this gene. Te R133C variant in the methylated-CpG-binding domain (MBD) of MeCP2 is the second most common disease-causing mutation in the MBD. Comparative molecular dynamics simulations of R133C mutant and wild-type MBD have been performed to understand the impact of the mutation on structure, dynamics, and interactions of the protein and subsequently understand the disease mechanism. Two salt bridges within the protein and two critical hydrogen bonds between the protein and DNA are lost upon the R133C mutation. Te mutation was found to weaken the interaction with DNA and also cause loss of helicity within the 141-144 region. Te structural, dynamical, and energetical consequences of R133C mutation were investigated in detail at the atomic resolution. Several important implications of this have been shown regarding protein stability and hydration dynamics as well as its interaction with DNA. Te results are in agreement with previous experimental studies and further provide atomic level understanding of the molecular origin of RTT associated with R133C variant. 1. Introduction Rett Syndrome (RTT) is an X-linked severe neurodevelop- mental disorder [1–5]. It is a progressive disease afer onset and especially afects the expressive language and hand use [6–10]. RTT afects 1 in 10,000 females with 20,000 RTT patients in the US and 50,000 worldwide [7]. Te mutations in MeCP2 are the major cause of RTT as they have been detected in more than 90% of classical RTT patients [8, 11]. In addition, the MeCP2 mutations are associated with X-linked mental retardation and other neurological disorders [8, 12]. MeCP2 is a member of the methyl-CpG-binding domain (MBD) family of proteins and has three major domains: the abovementioned MBD, the transcriptional repression domain (TRD), and the C-terminal domain (CTD). MeCP2 binds to symmetrical methylated 5  CpG pairs through its MBD with a preference for A/T-rich motifs [13]. It also belongs to intrinsically disordered family of proteins [14] and therefore binds to a number of other partners through its disordered regions, which span about 65% of the protein [15]. In general, MeCP2 serves diverse functions in gene regulation and chromatin organization and particularly it is a transcriptional repressor that mediates gene silencing through binding to methylated DNA [11]. However, recent studies indicate that it also can act as an activator [11]. In the body, it is distributed to all tissues but particularly abundant in brain [11]. Tere have been a number of RTT-causing mutations identifed at diferent regions of the 486-residue MeCP2 protein. Considering the mutations with a frequency of more than 0.05%, the 20% of the RTT cases are caused by mutations in the MBD domain of MeCP2. Also, the deleterious mutations are responsible for 27% of the cases and the missense mutations in parts of MeCP2 other than the MBD domain are responsible for 14% of RTT cases [16]. Here we focus on the mutations occurring in MBD and particularly studied here is the R133C mutation [17, 18]. Te Arg 133 is one of the two residues that make direct contacts Hindawi Publishing Corporation Computational and Mathematical Methods in Medicine Volume 2015, Article ID 746157, 9 pages http://dx.doi.org/10.1155/2015/746157