key: cord-284354-aoti88v7 authors: Lupala, Cecylia S.; Kumar, Vikash; Li, Xuanxuan; Su, Xiao-dong; Liu, Haiguang title: Computational analysis on the ACE2-derived peptides for neutralizing the ACE2 binding to the spike protein of SARS-CoV-2 date: 2020-05-04 journal: bioRxiv DOI: 10.1101/2020.05.03.075473 sha: doc_id: 284354 cord_uid: aoti88v7 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19, is spreading globally and has infected more than 3 million people. It has been discovered that SARS-CoV-2 initiates the entry into cells by binding to human angiotensin-converting enzyme 2 (hACE2) through the receptor binding domain (RBD) of its spike glycoprotein. Hence, drugs that can interfere the SARS-CoV-2-RBD binding to hACE2 potentially can inhibit SARS-CoV-2 from entering human cells. Here, based on the N-terminal helix α1 of human ACE2, we designed nine short peptides that have potential to inhibit SARS-CoV-2 binding. Molecular dynamics simulations of peptides in the their free and SARS-CoV-2 RBD-bound forms allow us to identify fragments that are stable in water and have strong binding affinity to the SARS-CoV-2 spike proteins. The important interactions between peptides and RBD are highlighted to provide guidance for the design of peptidomimetics against the SARS-CoV-2. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, also known as 2019-nCoV) 35 caused the COVID-19, which has been declared by the World Health Organization to be a global 36 pandemic. The COVID-19 has caused over 219,000 fatalities (as of April 29th, 2020) with more was also investigated in another study, which aims to develop molecules that interfere the binding 70 of SARS-CoV-2 RBD to hACE221. Their results showed that a 23-residue peptide (residues 21-71 43) of hACE2 N-terminal helix was able to bind to the RBD with nanomolar affinity, comparable 72 to that of full length hACE2. They also reported that a 12-residue peptide (residues 27-38) failed 73 to bind to the SARS-CoV-2 RBD. In a computational study, a 31-residue peptide derived from S19 A475 Q24 N487 T27 F456, A475, Y489 F28 Y489 D30 K417, F456 H34 Y453, L455 D38 Y449, G496 Y41 Q498, T500, N501 Q42 Q498, Y449 L45 Q498 M82 F486 Y83 F486, N487 forms. This observation suggests that those peptides prefer a similar helical conformation as they 195 were in the full hACE2 protein in solution, and the binding to the RBD resulted induced 196 conformational changes, which are more pronounced for shorter peptides, such as SIF8 and SIF9. Under the consideration of peptide stability, longer peptides are preferred according to the 198 simulation results. The SIF stability was also measured with their helicity contents in the free and bound forms (Table 200 2). The peptides SIF1 to SIF4 showed high helical contents (~80%) when they are in complex with 201 the spike protein RBD. It is interesting to observe that longer peptides tend to maintain stable helix to be effective in inhibiting the hACE2 binding. Figure 7 illustrates the binding energy 239 dependency on helical contents, especially the helicity of free peptides (solid black circles in 240 Figure 7) . Among the strong binders, whose binding energy are lower than -50 kcal/mol, there is 241 a shared sequence segment composed of the residues (24-39). 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