49. Zhu YM, Zhao WL, Fu JF, Shi JY, Pan Q, et al. (2006) NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis. Clin Cancer Res 12: 3043–3049. 50. Malecki MJ, Sanchez-Irizarry C, Mitchell JL, Histen G, Xu ML, et al. (2006) Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol Cell Biol 26: 4642–4651. 51. Nichols JT, Miyamoto A, Olsen SL, D’Souza B, Yao C, et al. (2007) DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol 176: 445–458. 52. Bush G, diSibio G, Miyamoto A, Denault JB, Leduc R, et al. (2001) Ligand- induced signaling in the absence of furin processing of Notch1. Dev Biol 229: 494–502. 53. Kelly DF, Lake RJ, Middelkoop TC, Fan HY, Artavanis-Tsakonas S, et al. (2010) Molecular structure and dimeric organization of the Notch extracellular domain as revealed by electron microscopy. PLoS ONE 5: e10532. 54. Miyazawa S, Jernigan RL (1996) Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. J Mol Biol 256: 623–644. 55. Karanicolas J, Brooks CL (2003) The structural basis for biphasic kinetics in the folding of the WW domain from a formin-binding protein: Lessons for protein design? Proc Natl Acad Sci U S A 100: 3954–3959. 56. Karanicolas J, Brooks CL (2004) Integrating folding kinetics and protein function: Biphasic kinetics and dual binding specificity in a WW domain. Proc Natl Acad Sci U S A 101: 3432–3437. 57. Hills RD, Brooks CL (2008) Subdomain competition, cooperativity, and topological frustration in the folding of CheY. J Mol Biol 382: 485–495. 58. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, et al. (1983) Charmm - a Program for Macromolecular Energy, Minimization, and Dynamics Calculations. J Comput Chem 4: 187–217. 59. Brooks BR, Brooks CL, Mackerell AD, Nilsson L, Petrella RJ, et al. (2009) CHARMM: The Biomolecular Simulation Program. J Comput Chem 30: 1545–1614. 60. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical-Integration of Cartesian Equations of Motion of a System with Constraints - Molecular- Dynamics of N-Alkanes. J Comput Phys 23: 327–341. 61. Paci E, Karplus M (2000) Unfolding proteins by external forces and temperature: The importance of topology and energetics. Proc Natl Acad Sci U S A 97: 6521–6526. Mechanosensing in Notch 62. Sugita Y, Okamoto Y (1999) Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett 314: 141–151. 63. Feig M, Karanicolas J, Brooks CL (2004) MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology. J Mol Graph Model 22: 377–395. 64. Im WP, Lee MS, Brooks CL (2003) Generalized born model with a simple smoothing function. J Comput Chem 24: 1691–1702. 65. Feig M, MacKerell AD, Brooks CL (2003) Force field influence on the observation of pi-helical protein structures in molecular dynamics simulations. J Phys Chem B 107: 2831–2836. 66. MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, et al. (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102: 3586–3616. 67. Mackerell AD, Feig M, Brooks CL (2004) Extending the treatment of backbone energetics in protein force fields: Limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J Comput Chem 25: 1400–1415. 68. MacKerell AD, Feig M, Brooks CL (2004) Improved treatment of the protein backbone in empirical force fields. J Am Chem Soc 126: 698–699. 69. Roux B, Simonson T (1999) Implicit solvent models. Biophysical Chemistry 78: 1–20. 70. Chen JH, Brooks CL, Khandogin J (2008) Recent advances in implicit solvent based methods for biomolecular simulations. Curr Opin Struc Biol 18: 140–148. 71. Khandogin J, Chen JH, Brooks CL (2006) Exploring atomistic details of pH- dependent peptide folding. Proc Natl Acad Sci U S A 103: 18546–18550. 72. Khandogin J, Brooks CL (2007) Linking folding with aggregation in Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci U S A 104: 16880–16885. 73. Khandogin J, Raleigh DP, Brooks CL (2007) Folding intermediate in the villin headpiece domain arises from disruption of a N-terminal hydrogen-bonded network. J Am Chem Soc 129: 3056–+. 74. Chen JH (2009) Intrinsically disordered p53 extreme C-terminus binds to S100B(betabeta) through ‘‘fly-casting’’. J Am Chem Soc 131: 2088–2089. 75. Ganguly D, Chen J (2009) Atomistic details of the disordered states of KID and pKID. implications in coupled binding and folding. J Am Chem Soc 131: 5214–5223. 76. Humphrey W, Dalke A, Schulten K (1996) VMD: Visual molecular dynamics. J Mol Graph 14: 33–&. PLoS ONE | www.plosone.org 11 July 2011 | Volume 6 | Issue 7 | e22837