A. Values-are-expressed-in, The distance SER@OG-HIS@NE2 shows the largest fluctuation for both subtilisins with known structure and for our models, consistent with variations of this distance in subtilisin crystal structures (Table 2) Catalytic triad: Asp316, His372, Ser549 Malaria vaccines and the new malaria agenda, Clin Microbiol Infect, vol.137, issue.17, pp.1600-1607, 2011.

S. Agnandji, B. Lell, S. Soulanoudjingar, J. Fernandes, and B. Abossolo, First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children, N Engl J Med, vol.365, pp.1863-1875, 2011.

H. Noedl, D. Socheat, and W. Satimai, Artemisinin-Resistant Malaria in Asia, New England Journal of Medicine, vol.361, issue.5, pp.540-541, 2009.
DOI : 10.1056/NEJMc0900231

P. Alonso, G. Brown, M. Arevalo-herrera, F. Binka, and C. Chitnis, A Research Agenda to Underpin Malaria Eradication, PLoS Medicine, vol.8, issue.1, p.1000406, 2011.
DOI : 10.1371/journal.pmed.1000406.s002

URL : https://hal.archives-ouvertes.fr/halshs-00681191

S. Mishra and C. Newton, Diagnosis and management of the neurological complications of falciparum malaria, Nature Reviews Neurology, vol.19, issue.4, pp.189-198, 2009.
DOI : 10.1038/nrneurol.2009.23

S. Yeoh, O. Donnell, R. Koussis, K. Dluzewski, A. Ansell et al., Subcellular Discharge of a Serine Protease Mediates Release of Invasive Malaria Parasites from Host Erythrocytes, Cell, vol.131, issue.6, pp.1072-1083, 2007.
DOI : 10.1016/j.cell.2007.10.049

L. Tawk, C. Lacroix, P. Gueirard, R. Kent, and O. Gorgette, A Key Role for Plasmodium Subtilisin-like SUB1 Protease in Egress of Malaria Parasites from Host Hepatocytes, Journal of Biological Chemistry, vol.288, issue.46, pp.33336-33346, 2013.
DOI : 10.1074/jbc.M113.513234

S. Zhu, T. Hudson, D. Kyle, and A. Lin, Synthesis and In Vitro Studies of Novel Pyrimidinyl Peptidomimetics as Potential Antimalarial Therapeutic Agents, Journal of Medicinal Chemistry, vol.45, issue.16, 2002.
DOI : 10.1021/jm020104f

A. Dagan, L. Efron, L. Gaidukov, A. Mor, and H. Ginsburg, In Vitro Antiplasmodium Effects of Dermaseptin S4 Derivatives, Antimicrobial Agents and Chemotherapy, vol.46, issue.4, pp.1059-1066, 2002.
DOI : 10.1128/AAC.46.4.1059-1066.2002

G. Smith and V. Petrenko, Phage Display, Chemical Reviews, vol.97, issue.2, pp.391-410, 1997.
DOI : 10.1021/cr960065d

M. He and M. Taussig, Ribosome display: Cell-free protein display technology, Briefings in Functional Genomics and Proteomics, vol.1, issue.2, pp.204-212, 2002.
DOI : 10.1093/bfgp/1.2.204

URL : http://bfg.oxfordjournals.org/cgi/content/short/1/2/204

R. Roberts and J. Szostak, RNA-peptide fusions for the in vitro selection of peptides and proteins, Proceedings of the National Academy of Sciences, vol.94, issue.23, pp.12297-12302, 1997.
DOI : 10.1073/pnas.94.23.12297

G. Bastianelli, A. Bouillon, C. Nguyen, E. Crublet, and S. Petres, Computational Reverse-Engineering of a Spider-Venom Derived Peptide Active Against Plasmodium falciparum SUB1, PLoS ONE, vol.4, issue.7, p.21812, 2011.
DOI : 10.1371/journal.pone.0021812.t004

A. Bouillon, D. Giganti, C. Benedet, O. Gorgette, and S. Petres, In Silico Screening on the Three-dimensional Model of the Plasmodium vivax SUB1 Protease Leads to the Validation of a Novel Anti-parasite Compound, Journal of Biological Chemistry, vol.288, issue.25, pp.18561-18573, 2013.
DOI : 10.1074/jbc.M113.456764

URL : https://hal.archives-ouvertes.fr/pasteur-01457905

A. Heitz, L. Chiche, D. Le-nguyen, and B. Castro, Proton 2D NMR and distance geometry study of the folding of Ecballium elaterium trypsin inhibitor, a member of the squash inhibitors family, Biochemistry, vol.28, issue.6, pp.2392-2398, 1989.
DOI : 10.1021/bi00432a009

D. Craik, N. Daly, and C. Waine, The cystine knot motif in toxins and implications for drug design, Toxicon, vol.39, issue.1, pp.43-60, 2001.
DOI : 10.1016/S0041-0101(00)00160-4

D. Craik, R. Clark, and N. Daly, Potential therapeutic applications of the cyclotides and related cystine knot mini-proteins, Expert Opinion on Investigational Drugs, vol.5, issue.5, pp.595-604, 2007.
DOI : 10.1021/bi002028t

H. Kolmar, Biological diversity and therapeutic potential of natural and engineered cystine knot miniproteins, Current Opinion in Pharmacology, vol.9, issue.5, pp.608-614, 2009.
DOI : 10.1016/j.coph.2009.05.004

D. Le-nguyen, H. Mattras, M. Coletti-previero, and B. Castro, Design and chemical synthesis of a 32 residues chimeric microprotein inhibiting both trypsin and carboxypeptidase A, Biochemical and Biophysical Research Communications, vol.162, issue.3, pp.1425-1430, 1989.
DOI : 10.1016/0006-291X(89)90833-4

A. Christmann, K. Walter, A. Wentzel, R. Kratzner, and H. Kolmar, The cystine knot of a squash-type protease inhibitor as a structural scaffold for Escherichia coli cell surface display of conformationally constrained peptides, Protein Engineering Design and Selection, vol.12, issue.9, pp.797-806, 1999.
DOI : 10.1093/protein/12.9.797

K. Hilpert, H. Wessner, J. Schneider-mergener, K. Welfle, and R. Misselwitz, Design and Characterization of a Hybrid Miniprotein That Specifically Inhibits Porcine Pancreatic Elastase, Journal of Biological Chemistry, vol.278, issue.27, pp.24986-24993, 2003.
DOI : 10.1074/jbc.M212152200

S. Reiss, M. Sieber, V. Oberle, A. Wentzel, and P. Spangenberg, Inhibition of platelet aggregation by grafting RGD and KGD sequences on the structural scaffold of small disulfide-rich proteins, Platelets, vol.2, issue.3, pp.153-157, 2006.
DOI : 10.2174/1389203043379477

A. Wentzel, A. Christmann, R. Kratzner, and H. Kolmar, Sequence Requirements of the GPNG ??-Turn of the Ecballium elaterium Trypsin Inhibitor II Explored by Combinatorial Library Screening, Journal of Biological Chemistry, vol.274, issue.30, pp.21037-21043, 1999.
DOI : 10.1074/jbc.274.30.21037

S. Lippow, K. Wittrup, and B. Tidor, Computational design of antibody-affinity improvement beyond in vivo maturation, Nature Biotechnology, vol.103, issue.10, pp.1171-1176, 2007.
DOI : 10.1038/nbt1336

R. Jha, A. Leaver-fay, S. Yin, Y. Wu, and G. Butterfoss, Computational Design of a PAK1 Binding Protein, Journal of Molecular Biology, vol.400, issue.2, pp.257-270, 2010.
DOI : 10.1016/j.jmb.2010.05.006

S. Chung and S. Subbiah, A structural explanation for the twilight zone of protein sequence homology, Structure, vol.4, issue.10, pp.1123-1127, 1996.
DOI : 10.1016/S0969-2126(96)00119-0

J. Otlewski, F. Jelen, M. Zakrzewska, and A. Oleksy, The many faces of protease???protein inhibitor interaction, The EMBO Journal, vol.8, issue.7, pp.1303-1310, 2005.
DOI : 10.1038/sj.emboj.7600611

S. Genheden and U. Ryde, How to obtain statistically converged MM/GBSA results, Journal of Computational Chemistry, vol.68, pp.837-846, 2010.
DOI : 10.1002/jcc.21366

T. Komiyama, B. Vanderlugt, M. Fugere, R. Day, and R. Kaufman, Optimization of protease-inhibitor interactions by randomizing adventitious contacts, Proceedings of the National Academy of Sciences, vol.100, issue.14, pp.8205-8210, 2003.
DOI : 10.1073/pnas.1032865100

K. Koussis, C. Withers-martinez, S. Yeoh, M. Child, and F. Hackett, A multifunctional serine protease primes the malaria parasite for red blood cell invasion, The EMBO Journal, vol.72, issue.6, pp.725-735, 2009.
DOI : 10.1016/j.cell.2007.10.049

N. Silmon-de-monerri, H. Flynn, M. Campos, F. Hackett, and K. Koussis, Global Identification of Multiple Substrates for Plasmodium falciparum SUB1, an Essential Malarial Processing Protease, Infection and Immunity, vol.79, issue.3, pp.1086-1097, 2011.
DOI : 10.1128/IAI.00902-10

N. Baker, D. Sept, S. Joseph, M. Holst, and J. Mccammon, Electrostatics of nanosystems: Application to microtubules and the ribosome, Proceedings of the National Academy of Sciences, vol.98, issue.18, pp.10037-10041, 2001.
DOI : 10.1073/pnas.181342398

H. Berman, J. Westbrook, Z. Feng, G. Gilliland, and T. Bhat, The Protein Data Bank, Nucleic Acids Research, vol.28, issue.1, pp.235-242, 2000.
DOI : 10.1093/nar/28.1.235

M. Feig, J. Karanicolas, and C. Brooks, MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology, Journal of Molecular Graphics and Modelling, vol.22, issue.5, p.3, 2004.
DOI : 10.1016/j.jmgm.2003.12.005

V. Hornak, R. Abel, A. Okur, B. Strockbine, and A. Roitberg, Comparison of multiple Amber force fields and development of improved protein backbone parameters, Proteins: Structure, Function, and Bioinformatics, vol.43, issue.3, pp.712-725, 2006.
DOI : 10.1002/prot.21123

W. Jorgensen, J. Chandrasekhar, and J. Madura, Comparison of simple potential functions for simulating liquid water, The Journal of Chemical Physics, vol.79, issue.2, p.926, 1983.
DOI : 10.1063/1.445869

J. Ryckaert, G. Ciccotti, and H. Berendsen, Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes, Journal of Computational Physics, vol.23, issue.3, pp.327-341, 1977.
DOI : 10.1016/0021-9991(77)90098-5

T. Darden, D. York, and L. Pederson, ) method for Ewald sums in large systems, The Journal of Chemical Physics, vol.98, issue.12, pp.10089-10092, 1993.
DOI : 10.1063/1.464397

D. Van-der-spoel, E. Lindahl, B. Hess, G. Groenhof, and A. Mark, GROMACS: Fast, flexible, and free, Journal of Computational Chemistry, vol.26, issue.16, pp.1701-1718, 2005.
DOI : 10.1002/jcc.20291

D. Ritchie and G. Kemp, Protein docking using spherical polar Fourier correlations, Proteins: Structure, Function, and Genetics, vol.3, issue.2, pp.178-194, 2000.
DOI : 10.1002/(SICI)1097-0134(20000501)39:2<178::AID-PROT8>3.0.CO;2-6

URL : https://hal.archives-ouvertes.fr/inria-00434273

H. Gohlke, C. Kiel, and D. Case, Insights into Protein???Protein Binding by Binding Free Energy Calculation and Free Energy Decomposition for the Ras???Raf and Ras???RalGDS Complexes, Journal of Molecular Biology, vol.330, issue.4, pp.891-913, 2003.
DOI : 10.1016/S0022-2836(03)00610-7

V. Tsui and D. Case, Theory and applications of the generalized born solvation model in macromolecular simulations, Biopolymers, vol.2, issue.4, pp.275-291, 2000.
DOI : 10.1002/1097-0282(2000)56:4<275::AID-BIP10024>3.0.CO;2-E

G. Ellman, Tissue sulfhydryl groups, Archives of Biochemistry and Biophysics, vol.82, issue.1, pp.70-77, 1959.
DOI : 10.1016/0003-9861(59)90090-6

M. Sajid, C. Withers-martinez, and M. Blackman, Maturation and Specificity of Plasmodium falciparum Subtilisin-like Protease-1, a Malaria Merozoite Subtilisin-like Serine Protease, Journal of Biological Chemistry, vol.275, issue.1, pp.631-641, 2000.
DOI : 10.1074/jbc.275.1.631

A. Debrabant, P. Maes, P. Delplace, J. Dubremetz, and A. Tartar, Intramolecular mapping of Plasmodium falciparum P126 proteolytic fragments by N-terminal amino acid sequencing, Molecular and Biochemical Parasitology, vol.53, issue.1-2, pp.89-96, 1992.
DOI : 10.1016/0166-6851(92)90010-H

W. Stafford, M. Blackman, A. Harris, S. Shai, and M. Grainger, N-terminal amino acid sequence of the Plasmodium falciparum merozoite surface protein-1 polypeptides, Molecular and Biochemical Parasitology, vol.66, issue.1, pp.157-160, 1994.
DOI : 10.1016/0166-6851(94)90048-5

H. Heidrich, A. Miettinin-bauman, C. Eckerskorn, and F. Lottspeich, The N-terminal amino acid sequences of the Plasmodium falciparum (FCB1) merozoite surface antigens of 42 and 36 kilodalton, both derived from the 185???195-kilodalton precursor, Molecular and Biochemical Parasitology, vol.34, issue.2, pp.147-154, 1989.
DOI : 10.1016/0166-6851(89)90006-6

O. Dea, K. Mckean, P. Harris, A. Brown, and K. , Processing of the Plasmodium chabaudi chabaudi AS merozoite surface protein 1 in vivo and in vitro, Molecular and Biochemical Parasitology, vol.72, issue.1-2, pp.111-119, 1995.
DOI : 10.1016/0166-6851(95)00090-N