Computational Mutagenesis of Antibody Fragments: Disentangling Side Chains from ΔΔ Predictions.

The development of highly potent antibodies and antibody fragments as binding agents holds significant implications in fields such as biosensing and biotherapeutics. Their binding strength is intricately linked to the arrangement and composition of residues at the binding interface. Computational techniques offer a robust means to predict the three-dimensional structure of these complexes and to assess the affinity changes resulting from mutations.

Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders.

Background: Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive.

Methods: We report five families carrying biallelic variants in PEX13.

Conformational Changes of Trialanine in Water Induced by Vibrational Relaxation of the Amide I Mode.

Most of the protein-based diseases are caused by anomalies in the functionality and stability of these molecules. Experimental and theoretical studies of the conformational dynamics of proteins are becoming in this respect essential to understand the origin of these anomalies. However, a description of the conformational dynamics of proteins based on mechano-energetic principles still remains elusive because of the intrinsic high flexibility of the peptide chains, the participation of weak noncovalent interactions, and the role of the ubiquitous water solvent.

Accurate Estimation of the Entropy of Rotation-Translation Probability Distributions.

The estimation of rotational and translational entropies in the context of ligand binding has been the subject of long-time investigations. The high dimensionality (six) of the problem and the limited amount of sampling often prevent the required resolution to provide accurate estimates by the histogram method. Recently, the nearest-neighbor distance method has been applied to the problem, but the solutions provided either address rotation and translation separately, therefore lacking correlations, or use a heuristic approach.

Distance-Based Configurational Entropy of Proteins from Molecular Dynamics Simulations.

Estimation of configurational entropy from molecular dynamics trajectories is a difficult task which is often performed using quasi-harmonic or histogram analysis. An entirely different approach, proposed recently, estimates local density distribution around each conformational sample by measuring the distance from its nearest neighbors. In this work we show this theoretically well grounded the method can be easily applied to estimate the entropy from conformational sampling.

A method for analyzing the vibrational energy flow in biomolecules in solution.

A method is proposed to analyze the intra- and intermolecular vibrational energy flow occurring in biomolecules in solution during relaxation processes. It is based on the assumption that the total energy exchanged between the vibrational modes is minimal and the global process is essentially statistical. This statistical minimum flow method is shown to provide very useful information about the amount and the rate at which energy is transferred between the individual vibrations of the molecule.

Instantaneous normal modes, resonances, and decay channels in the vibrational relaxation of the amide I mode of N-methylacetamide-D in liquid deuterated water.

A nonequilibrium molecular dynamics (MD) study of the vibrational relaxation of the amide I mode of deuterated N-methylacetamide (NMAD) in aqueous (D(2)O) solution is carried out using instantaneous normal modes (INMs). The identification of the INMs as they evolve over time, which is necessary to analyze the energy fluxes, is made by using a novel algorithm which allows us to assign unequivocally each INM to an individual equilibrium normal mode (ENM) or to a group of ENMs during the MD simulations. The time evolution of the energy stored in each INM is monitored and the occurrence of resonances during the relaxation process is then investigated.