The pre-tetramerization loop (PTL) of the human tumor suppressor protein p53 is an intrinsically disordered region (IDR) necessary for the tetramerization process, and its flexibility contributes to the essential conformational changes needed. Although the IDR can be accurately simulated in the traditional manner of molecular dynamics (MD) with the end-to-end distance (EEdist) unhindered, we sought to explore the effects of restraining the EEdist to the values predicted by electron microscopy (EM) and other distances. Simulating the PTL trajectory with a restrained EEdist , we found an increased agreement of nuclear magnetic resonance (NMR) chemical shifts with experiments. Additionally, we observed a plethora of secondary structures and contacts that only appear when the trajectory is restrained. Our findings expand the understanding of the tetramerization of p53 and provide insight into how mutations could make the protein impotent. In particular, our findings demonstrate the importance of restraining the EEdist in studying IDRs and how their conformations change under different conditions. Our results provide a better understanding of the PTL and the conformational dynamics of IDRs in general, which are useful for further studies regarding mutations and their effects on the activity of p53.

Division of Computational Chemistry Department of Chemistry Lund University P O Box 124 SE 221 00 Lund Sweden

Faculty of Pharmacy in Hradec Králové Charles University Akademika Heyrovského 1203 8 500 05 Hradec Králové Czech Republic

LINXS Institute of Advanced Neutron and 10 ray Science Scheelevägen 19 SE 233 70 Lund Sweden

MAX 4 Laboratory Lund Institute of Advanced Neutron and 10 ray Science Scheelevägen 19 SE 223 770 Lund Sweden

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