Article
Biochemistry & Molecular Biology
Thi-Thuy-Huong Le, Linh Hoang Tran, Minh Tam Nguyen, Minh Quan Pham, Huong Thi Thu Phung
Summary: Janus kinase 1 (JAK1) is a tyrosine kinase involved in cytokine responses. The similarity of ATP binding sites among JAK family members limits the selectivity of JAK1 inhibitors and may result in adverse effects. Computational methods can effectively identify JAK1 inhibitors with high binding affinity. The SMD/LIE method accurately predicts the binding free energies of JAK1 inhibitors and identifies promising inhibitors from marine fungal compounds.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Physical
Lauren Wickstrom, Emilio Gallicchio, Lieyang Chen, Tom Kurtzman, Nanjie Deng
Summary: Understanding the physical forces underlying receptor-ligand binding requires robust methods for analyzing the binding thermodynamics. This study presents a new end-point method called EE-BQH, which combines the Boltzmann-Quasiharmonic model with different solvation free energy methods to estimate the absolute binding free energy. Compared with other treatments of configurational entropy, EE-BQH shows higher accuracy in calculating the absolute binding free energy and demonstrates potential for providing insights in more complex protein-ligand systems.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Chemistry, Medicinal
Jorge Enrique Hernandez Gonzalez, Alexandre Suman de Araujo
Summary: This study presents a set of strategies, termed TIRST/TIRST-H+, to calculate the relative free energies of charge-changing mutations at protein-protein interfaces. The approaches combine thermodynamic integration with pK(a) shifts prediction, and special restraints are used to keep the transformed molecules separated. The accuracy of the methods was validated on a diverse data set, and the inclusion of variable protonation states improved the predicted Delta Delta G values.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Multidisciplinary Sciences
Fangqiang Zhu, Feliza A. Bourguet, William F. D. Bennett, Edmond Y. Lau, Kathryn T. Arrildt, Brent W. Segelke, Adam T. Zemla, Thomas A. Desautels, Daniel M. Faissol
Summary: Alchemical free energy perturbation (FEP) is a technique to calculate the free energy difference between chemical systems. This study implemented automated large-scale FEP calculations using the Amber software package for antibody design and evaluation. The FEP simulations aim to predict the effect of mutations on binding affinity and stability. Multiple strategies were incorporated to estimate the statistical uncertainties in the results. The study demonstrated the applicability of FEP in computational antibody design.
SCIENTIFIC REPORTS
(2022)
Review
Biochemical Research Methods
Debby D. Wang, Mengxu Zhu, Hong Yan
Summary: This paper reviews two classes of methods for accurately predicting protein-ligand binding affinities: free energy-based simulations and machine learning-based scoring functions. It follows thermodynamic cycles for the former and a feature-representation taxonomy for the latter. Additionally, recent deep learning-based predictions are also discussed, with comparisons of strengths, weaknesses, and future directions for improvements.
BRIEFINGS IN BIOINFORMATICS
(2021)
Article
Multidisciplinary Sciences
Megan L. Ken, Rohit Roy, Ainan Geng, Laura R. Ganser, Akanksha Manghrani, Bryan R. Cullen, Ursula Schulze-Gahmen, Daniel Herschlag, Hashim M. Al-Hashimi
Summary: Cellular processes are the result of interactions between biomolecules, which form biologically active complexes. These interactions are mediated by intermolecular contacts, and changes in biomolecule conformations are required for the formation of these contacts. Binding affinity and cellular activity depend on both the strength of the contacts and the propensities to form binding-competent conformational states. However, limitations have hindered the study of how conformational propensities affect cellular activity. This study focuses on the propensities of HIV-1 TAR RNA and how they predict binding affinities and cellular activity.
Article
Biochemistry & Molecular Biology
Fathima Ridha, A. Kulandaisamy, Michael Gromiha
Summary: Membrane protein complexes play a crucial role in various biological functions, but their binding affinity is less explored compared to globular proteins. Mutations in these complexes can affect binding affinity and impair critical functions, leading to diseases. To address this, the MPAD database was developed, providing experimental binding affinity data, sequence, structure, and functional information, membrane-specific features, experimental conditions, and literature information for membrane protein-protein complexes and mutants. MPAD can be used to understand the factors influencing binding affinity and the impact of mutations on membrane proteins, with potential applications in structure-based drug design.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Ilya A. Vakser, Sergei Grudinin, Nathan W. Jenkins, Petras J. Kundrotas, Eric J. Deeds
Summary: Computational methodologies are being used to model the entire cell at the molecular level. This study combines protein docking and molecular simulations to develop an approach that can simulate cellular processes at unprecedented timescales and all-atom resolution. The approach successfully captures the dynamics of protein interactions and has been validated across various protein systems.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Medicinal
Haochuan Chen, Han Liu, Heying Feng, Haohao Fu, Wensheng Cai, Xueguang Shao, Christophe Chipot
Summary: The study introduces a user-friendly tool called MLCV that facilitates the use of machine-learned CVs in importance-sampling simulations through the popular Colvars module. The approach is critically tested with three case examples involving small peptides, demonstrating the effectiveness of bridging deep learning and enhanced-sampling with MD simulations through hard-coded neural networks in Colvars.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemical Research Methods
Aditya K. Padhi, Ashutosh Kumar, Ken-Ichi Haruna, Haruna Sato, Hiroko Tamura, Satoru Nagatoishi, Kouhei Tsumoto, Atushi Yamaguchi, Fumie Iraha, Mihoko Takahashi, Kensaku Sakamoto, Kam Y. J. Zhang
Summary: Protein engineering using standard amino acids may limit functional diversity, but incorporating non-natural amino acids can improve the binding affinity of nanobodies towards cancer targets. Computational methods utilizing structure-based design have been developed to predict potent binders for disease-targets.
BRIEFINGS IN BIOINFORMATICS
(2021)
Article
Multidisciplinary Sciences
Hwankyu Lee
Summary: The simulations demonstrate strong binding between SARS-CoV-2 RBDs and antibodies, with slightly different binding strengths among antibodies. Polar uncharged residues of RBD are more likely to bind to antibodies compared to charged or hydrophobic residues, indicating a potential strategy for vaccine and drug design.
ADVANCED THEORY AND SIMULATIONS
(2021)
Article
Chemistry, Physical
Maria M. Reif, Martin Zacharias
Summary: This study presents an approach combining alchemical modifications and physical-pathway methods to calculate absolute binding free energies. It demonstrates the successful use of simultaneous alchemical transformations and physical ligand unbinding for potential of mean force calculations and nonequilibrium pulling simulations, as well as the benefits of reducing ligand-protein interactions prior to potential of mean force calculations. These methods show promise in reducing sampling problems and improving efficiency in protein-protein binding free energy calculations.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Multidisciplinary
Mario S. Valdes-Tresanco, Mario E. Valdes-Tresanco, Marcela Rubio-Carrasquilla, Pedro A. Valiente, Ernesto Moreno
Summary: This study parameterized four LIE models for estimating the binding free energy of Vps34-inhibitor complexes, all of which showed good predictive capacity and low mean absolute error. The LIE-D-derived models were highlighted for their advantages in predicting the weight of the different contributions to the binding free energy.
Review
Biochemistry & Molecular Biology
Edward King, Erick Aitchison, Han Li, Ray Luo
Summary: The grand challenge of structure-based drug design lies in accurately predicting binding free energies. Molecular dynamics simulations have enabled the modeling of conformational changes in the binding process, leading to the calculation of thermodynamic quantities for estimating binding affinities. Various approaches, including MM-PBSA, LIE, and alchemical methods, have been widely used to model molecular recognition for drug discovery and lead optimization.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Chemistry, Medicinal
Liang Qu, Xinyue Qiao, Fei Qi, Noritaka Nishida, Tyuji Hoshino
Summary: This study analyzed 500 antigen-antibody complex structures and found that Ser and Tyr are abundant in the complementarity-determining regions, with Tyr, Asp, Glu, and Arg making significant contributions to the molecular interaction. The average distance of the hydrogen bonds between the antigen and antibody was longer compared to compound-protein complexes, suggesting a looser interface in the antigen-antibody interaction.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)