Computational approach to design of aptamers to the receptor binding domain of SARS-CoV-2

This is a sel -a chi ed e sion o an o iginal a icle. This e sion may di e om he o iginal in pagina ion and ypog aphic de ails. Au ho (s): Ti le: Yea : Ve sion: Copy igh : Righ s: Righ s u l: Please ci e he o iginal e sion: CC BY 4.0 h ps://c ea i ecommons.o g/licenses/by/4.0/ Compu a ional app oach o design o ap ame s o he ecep o binding domain o SARS- CoV-2 © ARTYUSHENKO P. V., MIRONOV V. A., MOROZOV D. I., SHCHUGOREVA I. A., BORBONE N., TOMILIN F. N., KICHKAILO A. S. Published e sion A yushenko, P. V.; Mi ono , V. A.; Mo ozo , D. I.; Shchugo e a, I. A.; Bo bone, N.; Tomilin, F. N.; Kichkailo, A. S. A yushenko, P. V., Mi ono , V. A., Mo ozo , D. I., Shchugo e a, I. A., Bo bone, N., Tomilin, F. N., & Kichkailo, A. S. (2021). Compu a ional app oach o design o ap ame s o he ecep o binding domain o SARS-CoV-2. Sibi skoe Medicinskoe Oboz enie, 2021(2), 66-67. h ps://doi.o g/10.20333/2500136-2021-2-66-67 2021 66 © ARTYUSHENKO P. V., MIRONOV V. A., MOROZOV D. I., SHCHUGOREVA I. A., BORBONE N., TOMILIN F. N., KICHKAILO A. S. UDC 539.6 DOI: 10.20333/2500136-2021-2-66-67 Compu a ional app oach o design o ap ame s o he ecep o binding domain o SARS-CoV-2 P. V. A yushenko1,2, V. A. Mi ono 3, D. I. Mo ozo 4, I. A. Shchugo e a1,2, N. Bo bone5, F. N. Tomilin2,6, A. S. Kichkailo1 1Fede al Resea ch Cen e KSC SB RAS, K asnoya sk 660036, Russian Fede a ion 2Sibe ian Fede al Uni e si y, K asnoya sk 660041, Russian Fede a ion 3Lomonoso Moscow S a e Uni e si y, Moscow 119991, Russian Fede a ion 4Uni e si y o Jy äskylä, Jy äskylä 40014, Finland 5Uni e si y o Naples Fede ico II, Naples 80138, I aly 6Ki ensky Ins i u e o Physics KSC SB RAS, K asnoya sk 660036, Russian Fede a ion Th e aim o he esea ch. In his wo k, in silico selec ion o DNA-ap ame s o he ecep o -binding domain (RBD) o he SARS-CoV-2 spike p o ein was pe o med using molecula modeling me hods. Ma e ial and me hods. A new compu a ional app oach o ap ame in silico selec ion is based on a cycle o simula ions, including he s ages o molecula modeling, molecula docking, molecula dynamic simula ions, and quan um chemical calcula ions. To e i y he ob ained calcula ed esul s l ow cy ome y, l uo escence pola iza ion, and small-angle X- ay sca e ing me hods we e applied. Resul s. An ini ial lib a y consis ed o 256 16-me oligonucleo ides was modeled. Based on molecula docking esul s, he only one ap ame (Ap 16) was selec ed om he lib a y as a s a ing ap ame o he RBD p o ein. Fo Ap 16/RBD complex, molecula dynamic and quan um chemical calcula ions e ealed he pai s o nucleo ides and amino acids whose con ibu ion o he binding be ween ap ame and RBD is he la ges . Taking in o accoun hese da a, Ap 16 was subjec ed o he s uc u e modi i ca ions in o de o inc ease he binding wi h he RBD. Th us, a new ap ame Ap 25 was designed. Th e p ocedu e o 1) ap ame s uc u e modeling/modi i ca ion, 2) molecula docking, 3) molecula dynamic simula ions, 4) quan um chemical calcula ions was pe o med se - e al imes. As a esul , ou ap ame s (Ap 16, Ap 25, Ap 27, Ap 31) o he RBD we e designed in silico wi hou any p elimina y expe imen al da a. Binding o he each modeled ap ame o he RBD was s udied in e ms o in e ac ions be ween esidues in p o ein and nucleo ides in he ap ame s. Based on he simula ion esul s, he s onges binding wi h he RBD was p edic ed o wo Ap 27 and Ap 31ap ame s. Th e calcula ed esul s a e in good ag eemen wi h expe imen al da a ob ained by l ow cy ome y, l uo escence pola iza ion, and small-angle X- ay sca e ing me hods. Conclusion. Th e p oposed compu a ional app oach o selec ion and e i nemen o ap ame s is uni e sal and can be used o wide ange o molecula ligands and a ge s. Key wo ds: selec ion, ap ame , ecep o -binding domain, SARS-CoV-2. Con l ic o in e es . Th e au ho s decla e he absence o ob ious and po en ial con l ic s o in e es associa ed wi h he publica ion o his a icle. Ci a ion: A yushenko PV, Mi ono VA, Mo ozo DI, Shchugo e a IA, Bo bone N, Tomilin FN, Kichkailo AS. Compu a ional app oach o design o ap am- e s o he ecep o binding domain o SARS-CoV-2. Sibe ian Medical Re iew. 2021; (2):66-67. DOI: 10.20333/2500136-2021-2-66-67 Материалы конференции / Сon e ence p oceedings 5-й Международный семинар «Цифровые лекарства на стыке наук» 5 h Join Semina wi h In e na ional Pa icipa ion"Digi al Medicines a he In e sec ion o Sciences" Selec ion o DNA-ap ame s o he ecep o -binding domain (RBD) o he SARS-CoV-2 spike p o ein was pe o med using a no el app oach based on he com- pu a ional molecula modeling. A i s s age o in silico ap ame selec ion, he ini ial lib a y o he ap ame can- dida es was designed. A 16-me hai pin loop was chosen as he s a ing s uc u e o he ap ame . Th e double helix 5’-GGAATT-loop-AATTCC-3’ was p oposed as he con- s an s em pa o he ap ame s. Th e a iable loop pa was o med by ou “NNNN” nucleo ides. Taking in o accoun all possible combina ions o he DNA nucleo ides, 256 s uc u es was ob ained as ini ial ap ame lib a y. A second s age, he molecula docking o all 256 models was pe o med using HDOCK webse e [1]. As a po en ial binding si e, he conca e uppe egion o he RBD p o ein was conside ed. Based on docking esul s, he ap ame candida e, which was p edic ed o bind wi h he uppe pa o he RBD, was selec ed. Th a 16me wi h AGTC nucleo ides in he loop pa (Ap 16) was chosen as he s a ing sequence o u he s uc u e modi i ca ions Sibe ian Medical Re iew. 2021;(2):66-67 Compu a ional app oach o design o ap ame s o he ecep o binding domain o SARS-CoV-2A yushenko P. V., Mi ono V. A., Mo ozo D. I. e al. 67 in o de o imp o e he binding a i ni y o he RBD. Nex , he Ap 16/RBD complex was subjec ed o he de ailed analysis using molecula dynamic (MD) and quan um chemical simula ions. MD simula ions we e conduc ed by using GROMACS 2019.8 so wa e [2]. A e MD he Ap 16/RBD complex s uc u e was op imized wi h FMO- DFTB/PCM [3, 4]. Fo he op imized s uc u es, FMO agmen a ion app oach was used o ob ain he in e ac- ion ene gies, which we e e alua ed wi h non-empi ical RI-MP2/6-31G (d,p) me hod [5]. Th e o al in e ac ion ene gy E o al be ween RBD and ap ame (Table) and he pa ial con ibu ion o he binding ene gy om single nu- cleo ide in he ap ame we e es ima ed using hese com- pu a ional me hods. Table To al in e ac ion ene gy E o al (kcal mol-1) and he numbe o hyd ogen bonds NHB be ween ap ame s and RBD Ap ame * NHB E o al Ap ame * NHB E o al Ap 16 12 -153.0 Ap 27 17 -217.4 Ap 25 12 -162.7 Ap 31 13 -221.6 Based on he ob ained calcula ed esul s, he s uc- u e o he Ap 16 was modi i ed in o de o imp o e he a i ni y and speci i ci y o he ap ame binding o he RBD p o ein. Th us, a new ap ame Ap 25 5’-CCTAG- GAATT-TGTCT-AATTCCTAGG-3’ was modeled. Th e same compu a ional simula ions desc ibed abo e o Ap 16 was pe o med o Ap 25. Compa ison o he cal- cula ion esul s o RBD/Ap 16 and RBD/Ap 25 complex- es con i med ha he ap ame s uc u e modi i ca ions imp o e binding. Th e in silico selec ion scheme, which include ap ame s uc u e modeling (modi i ca ion), mo- lecula docking, MD, and quan um chemical calcula ions, was applied a se e al imes. As a esul , wo new ap ame s we e c ea ed: Ap 27 5’-CGGATGGAAT-TTG TCTG-AT- TCCATCCG-3’ and Ap 31 5’-CGGATGGAAT-ACTT TGTC TGTC-ATTCCATCCG -3’. Th e esul s o simula- ions o all ap ame s, Ap 16, Ap 25, Ap 27, and Ap 31, a e shown in Table 1. Th e binding o he heo e ically modeled ap ame s o he RBD p o ein was con i med ex- pe imen ally by l ow cy ome y, l uo escence pola iza ion, and small-angle X- ay sca e ing me hods. Th e p oposed scheme o in silico ap ame selec ion can be applied o a wide ange o ligands and p o ein a ge s. Re e ences 1. Yan Y, Zhang D, Zhou P, Li B, Huang SY. HDOCK: a web se e o p o ein-p o ein and p o ein-DNA/RNA docking based on a hyb id s a egy. Nucleic Acids Re- sea ch. 2017; (45):365-373. 2. Ab aham MJ, Mu ola T, Schulz R, P'all S, Smi h JC, Hess B, Lindah E. G omacs: High pe o mance molecula simula ions h ough mul i-le el pa allelism om lap ops o supe compu e s. So wa eX. 2015; (1-2):19-25. 3. Fedo o D.G. Th e agmen molecula o bi al me hod: Th eo e ical de elopmen , implemen a ion in GAMESS, and applica ions. Wiley In e disciplina y Re- iews: Compu a ional Molecula Science. 2017; (7):1-17. 4. Gaus M, Goez A, Els ne M. Pa ame iza ion and Benchma k o DFTB3 o O ganic Molecules. Jou nal o Chemical Th eo y and Compu a ion. 2013; (9):338–354. 5. Fedo o DG, Ki au a K. Pai in e ac ion ene gy de- composi ion analysis. Jou nal o Compu a ional Chemis- y. 2007; (28):222-237. Au ho in o ma ion Polina V. A yushenko, Candida e o Sciences in Physics and Ma hema ics, senio esea che , Labo a o y o Digi al Con olled D ugs and Th e anos ics, Fede al Resea ch Cen e ”K asnoya sk Science Cen e SB RAS”; Add ess: 50, Akademgo odok, K asnoya sk, Russian Fede a ion 660036; Depa men o Chemis y, Sibe ian Fede al Uni e si y; Add ess: 79, S obodny p , K asnoya sk, Russian Fede a ion 660041; Phone: +79082005639; e-mail: a _polly@mail. u, h ps://o cid.o g/0000-0002-3176-8202 Vladimi A. Mi ono , Candida e o Sciences in Physics and Ma hema ics, senio esea che , Depa men o Chemis y, Lomonoso Moscow S a e Uni e si y; Add ess: Leninskie Go y, Moscow, Russian Fede a ion 119234; Phone: +7(495)9391671, e-mail: ladimi .a.mi ono @ gmail.com, h ps://o cid.o g/0000-0002-9454-5823 Dmi y I. Mo ozo , Candida e o Sciences in Chemis y, Pos doc o al Resea che , Nanoscience Cen e and Depa men o Chemis y, Uni e si y o Jy äskylä; Add ess: PO Box 35, Jy äskylä, Republic o Finland 40014; Phone: +358142601211, e-mail: dmi y.mo [email p o ec ed] , h ps://o cid.o g/0000-0001-9524-948X I ina A. Shchugo e a, junio esea che , Labo a o y o Digi al Con olled D ugs and Th e anos ics, Fede al Resea ch Cen e ”K asnoya sk Science Cen e SB RAS”; Add ess: 50, Akademgo odok, K asnoya sk, Russian Fede a ion 660036; Depa men o Chemis y, Sibe ian Fede al Uni e si y; Add ess: 79, S obodny p , K asnoya sk, Russian Fede a ion 660041; Phone: +7-902-969-11-54; e-mail: shchugo e ai@mail. u, h ps://o cid.o g/0000-0003-4207-1627 Nicola Bo bone, Doc o o Philosophy, Uni e si y o Naples Fede ico II; Add ess:, 49 Via Domenico Mon esano, Napoli, I aly 80131; Phone: +39 081 678521; e-mail: nicola.bo bone@ unina.i , h ps://o cid.o g/0000-0003-0216-9814 Felix N. Tomilin, Candida e o Sciences in Chemis y, associa e p o esso , Depa men o Chemis y, Sibe ian Fede al Uni e si y; Add ess: 79, S obodny p , K asnoya sk, Russian Fede a ion 660041; Add ess: 50/38 Akademgo odok, K asnoya sk, Russian Fede a ion 660036; Phone: +79509788890; e-mail: elixn[email p o ec ed], h ps://o cid.o g/0000-0002-3578-6141 Anna. S. Kichkailo, Doc o o Sciences in Biology, leading esea che , Labo a o y o Digi al Con olled D ugs and Th e anos ics, Fede al Resea ch Cen e ”K asnoya sk Science Cen e SB RAS”; Add ess: 50, Akademgo odok, K asnoya sk, Russian Fede a ion 660036; Phone: +79039238402; e-mail: annazamay@yandex. u, h ps://o cid.o g/0000-0003-1054- 4629 Recei ed 16 Feb ua y 2021 Re ision Recei ed 18 Ma ch 2021 Accep ed 31 Ma ch 2021 Сибирское медицинское обозрение. 2021;(2):66-67 Материалы конференции Сon e ence p oceedings