Molecular mechanics/Poisson–Boltzmann (Generalized-Born) surface area is one of the most popular methods to estimate binding free energies. This method has been proven to balance accuracy and computational efficiency, especially when dealing with large systems. As a result of its popularity, several programs have been developed for performing MM/PB­(GB)­SA calculations within the GROMACS community. These programs, however, present several limitations. Here we present gmx_MMPBSA, a new tool to perform end-state free energy calculations from GROMACS molecular dynamics trajectories. gmx_MMPBSA provides the user with several options, including binding free energy calculations with different solvation models (PB, GB, or 3D-RISM), stability calculations, computational alanine scanning, entropy corrections, and binding free energy decomposition. Noteworthy, several promising methodologies to calculate relative binding free energies such as alanine scanning with variable dielectric constant and interaction entropy have also been implemented in gmx_MMPBSA. Two additional toolsgmx_MMPBSA_test and gmx_MMPBSA_anahave been integrated within gmx_MMPBSA to improve its usability. Multiple illustrating examples can be accessed through gmx_MMPBSA_test, while gmx_MMPBSA_ana provides fast, easy, and efficient access to different graphics plotted from gmx_MMPBSA output files. The latest version (v1.4.3, 26/05/2021) is available free of charge (documentation, test files, and tutorials included) at .

AMDock (Assisted Molecular Docking) is a user-friendly graphical tool to assist in the docking of protein-ligand complexes using Autodock Vina and AutoDock4, including the option of using the Autodock4Zn force field for metalloproteins. AMDock integrates several external programs (Open Babel, PDB2PQR, AutoLigand, ADT scripts) to accurately prepare the input structure files and to optimally define the search space, offering several alternatives and different degrees of user supervision. For visualization of molecular structures, AMDock uses PyMOL, starting it automatically with several predefined visualization schemes to aid in setting up the box defining the search space and to visualize and analyze the docking results. One particularly useful feature implemented in AMDock is the off-target docking procedure that allows to conduct ligand selectivity studies easily. In summary, AMDock’s functional versatility makes it a very useful tool to conduct different docking studies, especially for beginners. The program is available, either for Windows or Linux, at https://github.com/Valdes-Tresanco-MS. Reviewers This article was reviewed by Alexander Krah and Thomas Gaillard.

Blocking the association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) is an attractive therapeutic approach to prevent the virus from entering human cells. While antibodies and other modalities have been developed to this end, d -amino acid peptides offer unique advantages, including serum stability, low immunogenicity, and low cost of production. Here, we designed potent novel D-peptide inhibitors that mimic the ACE2 α1-binding helix by searching a mirror-image version of the PDB. The two best designs bound the RBD with affinities of 29 and 31 nM and blocked the infection of Vero cells by SARS-CoV-2 with IC 50 values of 5.76 and 6.56 μM, respectively. Notably, both D-peptides neutralized with a similar potency the infection of two variants of concern: B.1.1.7 and B.1.351 in vitro . These potent D-peptide inhibitors are promising lead candidates for developing SARS-CoV-2 prophylactic or therapeutic treatments.

In this work, we introduced an improved linear interaction energy (LIE) method parameterization for computations of protein–ligand binding free energies. The protocol, coined LIE-D, builds on the linear relationship between the empirical coefficient γ in the standard LIE scheme and the D parameter, introduced in our work. The D-parameter encompasses the balance (difference) between electrostatic (polar) and van der Waals (nonpolar) energies in protein–ligand complexes. Leave-one-out cross-validation showed that LIE-D reproduced accurately the absolute binding free energies for our training set of protein–ligand complexes (<|error|> = 0.92 kcal/mol, SDerror = 0.66 kcal/mol, R(2) = 0.90, QLOO(2) = 0.89, and sPRESS(LOO) = 1.28 kcal/mol). We also demonstrated LIE-D robustness by predicting accurately the binding free energies for three different protein–ligand systems outside the training data set, where the electrostatic and van der Waals interaction energies were calculated with different force fields.

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The sea anemone Stichodactyla helianthus produces two pore-forming proteins, sticholysins I and II (St I and St II). Despite their high identity (93%), these toxins exhibit differences in hemolytic activity that can be related to those found in their N-terminal. To clarify the contribution of the N-terminal amino acid residues to the activity of the toxins, we synthesized peptides spanning residues 1-31 of St I (StI 1-31 ) or 1-30 of St II (StII ) and demonstrated that StII 1-30 promotes erythrocyte lysis to a higher extent than StI 1-31 . For a better understanding of the molecular mechanism underlying the peptide activity, here we studied their binding to lipid monolayers and pemeabilizing activity in liposomes. For this, we examined the effect on peptide membranotropic activity of including phospatidic acid and cholesterol in a lipid mixture of phosphatidylcholine and sphingomyelin. The results suggest the importance of continuity of the 1-10 hydrophobic sequence in StII 1-30 for displaying higher binding and activity, in spite of both peptides' abilities to form pores in giant unilamellar vesicles. Thus, the different peptide membranotropic action is explained in terms of the differences in hydrophobic and electrostatic peptide properties as well as the enhancing role of membrane inhomogeneities.[Ros U, Pedrera L, Díaz D, de Karam JC, Sudbrack TP, Valiente PA, Martínez D, Cilli EM, Pazos F, Itri R, Lanio ME, Schreier S and Álvarez C 2011 The membranotropic activity of N-terminal peptides from the pore-forming proteins sticholysin I and II is modulated by hydrophobic and electrostatic interactions as well as lipid composition. J.

The standard parameterization of the Linear Interaction Energy (LIE) method has been applied with quite good results to reproduce the experimental absolute binding free energies for several protein-ligand systems. However, we found that this parameterization failed to reproduce the experimental binding free energy of Plasmepsin II (PlmII) in complexes with inhibitors belonging to four dissimilar scaffolds. To overcome this fact, we developed three approaches of LIE, which combine systematic approaches to predict the inhibitor-specific values of α, β, and γ parameters, to gauge their ability to calculate the absolute binding free energies for these PlmII-Inhibitor complexes. Specifically: (i) we modified the linear relationship between the weighted nonpolar desolvation ratio (WNDR) and the α parameter, by introducing two models of the β parameter determined by the free energy perturbation (FEP) method in the absence of the constant term γ, and (ii) we developed a new parameterization model to investigate the linear correlation between WNDR and the correction term γ. Using these parameterizations, we were able to reproduce the experimental binding free energy from these systems with mean absolute errors lower than 1.5 kcal/mol.

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