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On the determinants of electron transfer reorganization energy in a cytochrome P450: cytochrome b5 complex. A combined quantum mechanics and molecular dynamics simulation study

Abstract (Expand)

The electron transfer steps in the catalytic cycle of cytochrome P450 (CYP) enzymes, ubiquitous proteins with key roles in processes such as drug metabolism and steroidogenesis, are often rate-limiting. …rate-limiting. To predict ET rates from atomistic molecular dynamics simulations using Marcus theory, values of the reaction free energy ΔG0 and the reorganization free energy λ are required from either experiments or computations. For the reduction of cytochrome P450 17A1 (CYP17A1) by the secondary redox protein cytochrome b5 (CYb5), a critical step in the regulation of steroidogenesis, experimental measurements of λ are not available. We here describe the computation of λ for this system from a combination of molecular mechanics/molecular dynamics simulations and quantum mechanics computations. Our results show that a quantum mechanical treatment of the redox-active cofactors is necessary, even though the surrounding protein and solvent, which are modeled classically, contribute most to the reorganization energy. The values of λ computed for structural ensembles corresponding to two predicted binding modes of the proteins are 1.23 and 1.16 eV. We find that the λ values computed for the individual soluble globular domains of the two proteins sum to approximately the λ values computed for the membrane-bound CYP17A1-CYb5 complex, indicating that additivity can be invoked in a computationally efficient approach to estimating λ values for such protein–protein complexes.

Authors: J. Teuffel, G. Mukherjee, S. B. Han, M. Elstner, R. C. Wade

Date Published: 21st May 2025

Publication Type: Journal

Simulation of Neurotrophin Receptor Transmembrane Helix Interactions Reveals Active States and Distinct Signaling Mechanisms

Abstract

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Authors: Christina Athanasiou, Ainara Claveras Cabezudo, Alexandros Tsengenes, Rebecca C. Wade

Date Published: 27th Apr 2025

Publication Type: Journal

Design of nanobody targeting SARS-CoV-2 spike glycoprotein using CDR-grafting assisted by molecular simulation and machine learning

Abstract (Expand)

The design of proteins capable effectively binding to specific protein targets is crucial for developing therapies, diagnostics, and vaccine candidates for viral infections. Here, we introduce a …we introduce a complementarity-determining region (CDR) grafting approach for designing nanobodies (Nbs) that target specific epitopes, with the aid of computer simulation and machine learning. As a proof-of-concept, we designed, evaluated, and characterized a high-affinity Nb against the spike protein of SARS-CoV-2, the causative agent of the COVID-19 pandemic. The designed Nb, referred to as Nb Ab.2, was synthesized and displayed high-affinity for both the purified receptor-binding domain protein and to the virus-like particle, demonstrating affinities of 9 nM and 60 nM, respectively, as measured with microscale thermophoresis. Circular dichroism showed the designed protein’s structural integrity and its proper folding, whereas molecular dynamics simulations provided insights into the internal dynamics of Nb Ab.2. This study shows that our computational pipeline can be used to efficiently design high-affinity Nbs with diagnostic and prophylactic potential, which can be tailored to tackle different viral targets.

Authors: Matheus VF Ferraz, W Camilla S Adan, Tayná E Lima, Adriele JC Santos, Sérgio O de Paula, Rafael Dhalia, Gabriel L Wallau, Rebecca C Wade, Isabelle FT Viana, Roberto D Lins

Date Published: 21st Apr 2025

Publication Type: Journal

Prediction of drug-protein binding kinetics

Abstract

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Author: Abraham Muñiz‐Chicharro

Date Published: 3rd Apr 2025

Publication Type: Doctoral Thesis

The need to implement FAIR principles in biomolecular simulations.

Abstract

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Authors: R. E. Amaro, J. Aqvist, I. Bahar, F. Battistini, A. Bellaiche, D. Beltran, P. C. Biggin, M. Bonomi, G. R. Bowman, R. A. Bryce, G. Bussi, P. Carloni, D. A. Case, A. Cavalli, C. A. Chang, T. E. 3rd Cheatham, M. S. Cheung, C. Chipot, L. T. Chong, P. Choudhary, G. A. Cisneros, C. Clementi, R. Collepardo-Guevara, P. Coveney, R. Covino, T. D. Crawford, M. Dal Peraro, B. L. de Groot, L. Delemotte, M. De Vivo, J. W. Essex, F. Fraternali, J. Gao, J. L. Gelpi, F. L. Gervasio, F. D. Gonzalez-Nilo, H. Grubmuller, M. G. Guenza, H. V. Guzman, S. Harris, T. Head-Gordon, R. Hernandez, A. Hospital, N. Huang, X. Huang, G. Hummer, J. Iglesias-Fernandez, J. H. Jensen, S. Jha, W. Jiao, W. L. Jorgensen, S. C. L. Kamerlin, S. Khalid, C. Laughton, M. Levitt, V. Limongelli, E. Lindahl, K. Lindorff-Larsen, S. Loverde, M. Lundborg, Y. L. Luo, F. J. Luque, C. I. Lynch, A. D. Jr MacKerell, A. Magistrato, S. J. Marrink, H. Martin, J. A. McCammon, K. Merz, V. Moliner, A. J. Mulholland, S. Murad, A. N. Naganathan, S. Nangia, F. Noe, A. Noy, J. Olah, M. L. O'Mara, M. J. Ondrechen, J. N. Onuchic, A. Onufriev, S. Osuna, G. Palermo, A. R. Panchenko, S. Pantano, C. Parish, M. Parrinello, A. Perez, T. Perez-Acle, J. R. Perilla, B. M. Pettitt, A. Pietropaolo, J. P. Piquemal, A. B. Poma, M. Praprotnik, M. J. Ramos, P. Ren, N. Reuter, A. Roitberg, E. Rosta, C. Rovira, B. Roux, U. Rothlisberger, K. Y. Sanbonmatsu, T. Schlick, A. K. Shaytan, C. Simmerling, J. C. Smith, Y. Sugita, K. Swiderek, M. Taiji, P. Tao, D. P. Tieleman, I. G. Tikhonova, J. Tirado-Rives, I. Tunon, M. W. van der Kamp, D. van der Spoel, S. Velankar, G. A. Voth, R. Wade, A. Warshel, V. V. Welborn, S. D. Wetmore, T. J. Wheeler, C. F. Wong, L. W. Yang, M. Zacharias, M. Orozco

Date Published: 2nd Apr 2025

Publication Type: Journal

Prediction of Binding Kinetics of the Interleukin-13-Interleukin-13 Receptor alpha1 Complex

Abstract

Not specified

Editor:

Date Published: 31st Jan 2025

Publication Type: Master's Thesis

Structural bioinformatics approach to exploring transient binding pockets in proteins

Abstract

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Editor:

Date Published: 18th Dec 2024

Publication Type: Bachelor's Thesis

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