By the end of the course, students will be able to: Molecular mechanics and physical foundations ● Interpret proteins, membranes, and nucleic acids as mechanical objects — structures that store elastic energy, transmit forces, and undergo conformational transitions under load. ● Apply statistical mechanics and force field theory to describe atomic interactions and predict molecular behaviour. Computational workflow ● Set up, run, and analyse molecular dynamics simulations of biomolecules using GROMACS in a Linux environment. ● Perform steered molecular dynamics to compute force-extension curves and characterise the rate-dependent mechanical response of biomolecules. ● Apply enhanced sampling methods and free energy calculations to explore conformational landscapes and quantify binding energetics. Structural and network analysis ● Use normal mode analysis, functional mode analysis, and dynamic correlation methods to identify mechanically relevant motions in proteins and assemblies. ● Apply Protein Structure Network (PSN) analysis to map pathways of mechanical signal propagation and allosteric communication. Critical reading and application ● Read and discuss primary literature on molecular biomechanics, connecting simulation results to biological and clinical questions. ● Apply the acquired workflow to case studies from current research, including membrane mechanics, drug delivery systems, protein dynamics in disease, and nucleic acid mechanics.

Students are expected to have a solid background in classical mechanics, thermodynamics, linear algebra, and introductory biology and chemistry. Basic programming experience is helpful but not required. No prior knowledge of molecular simulation or computational biology is assumed. The lecturer will address specific background gaps through dedicated lectures, and students are guided through the computational environment from the first laboratory session.

Introduction Introduction to the course and overview of molecular biomechanics Introduction to molecular modelling: concepts, scales, and applications Biomolecules as mechanical objects: proteins, membranes, and nucleic acids Physical foundations Molecular driving forces: thermodynamics and statistical mechanics applied to biological systems From quantum to classical mechanics: approximations and the basis of force fields Ball-and-spring models and the harmonic approximation Molecular mechanics Bonded and non-bonded interactions: functional forms and parameterisation Long-range interactions: electrostatics, cutoffs, and Ewald summation Simulating the environment: implicit and explicit solvent, periodic boundary conditions Energy minimisation: algorithms and convergence Simulation methods Molecular dynamics: equations of motion, integrators, thermostats, and barostats Monte Carlo methods: sampling strategies and acceptance criteria Steered molecular dynamics: computational mechanical testing, force-extension curves, and rate-dependent response Enhanced sampling methods: metadynamics, replica exchange, and parallel tempering Free energy calculations: thermodynamic integration, umbrella sampling, and non-equilibrium approaches Structural and network analysis Normal mode analysis: global mechanical modes in proteins and assemblies Functional mode analysis and dynamic cross-correlation Protein Structure Network (PSN) analysis: mechanical signal propagation and allosteric pathways Multiscale methods Coarse-grained modelling: principles and applications to large biological assemblies Applications Case studies from primary literature, connecting the computational methods of the course to current biomedical research. Examples include membrane mechanics and protein-membrane interactions, nanovector design for drug delivery, protein-ligand binding mechanics and kinetics, protein misfolding and aggregation in neurodegeneration and cancer, and nucleic acid mechanics and RNA folding. Specific examples may be updated from year to year. Laboratory A significant part of the course is dedicated to computational laboratory sessions. Students work in a Linux environment set up within Visual Studio Code, which provides an integrated and portable workspace for running simulations, scripting workflows, and managing output files. Molecular dynamics simulations are performed with GROMACS (GROningen MAchine for Chemical Simulations), one of the most widely used and high-performance open-source packages for biomolecular simulation, with an extensive community and documentation. Molecular structures and trajectories are visualised and analysed with VMD (Visual Molecular Dynamics). Laboratory sessions cover: ● Linux environment and Bash scripting for simulation setup and automation ● Energy minimisation and equilibrium molecular dynamics with GROMACS ● Steered molecular dynamics and force-extension curve analysis ● Simulated annealing and conformational sampling ● Equilibrium and non-equilibrium trajectory analysis ● Molecular visualisation and structural analysis with VMD

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Lectures, classroom exercises, paper-based seminars, and hands-on sessions in computational lab.

The teacher will provide all the course material (slides and lecture notes). Suggested textbooks: ● Dill, K.A., Bromberg, S., 2010. Molecular Driving Forces: Statistical Thermodynamics in Biology, Chemistry, Physics, and Nanoscience. 2nd ed. Garland Science. ● Frenkel, D., Smit, B., 2002. Understanding Molecular Simulation: From Algorithms to Applications. 2nd ed. Academic Press. ● Leach, A.R., 2001. Molecular Modelling: Principles and Applications. Prentice Hall. ● Schlick, T., 2010. Molecular Modeling and Simulation: An Interdisciplinary Guide. 2nd ed. Springer. ● Nelson, P., 2008. Biological Physics: Energy, Information, Life. W.H. Freeman. ● Chipot, C., Pohorille, A. (eds.), 2007. Free Energy Calculations: Theory and Applications in Chemistry and Biology. Springer.

Lecture slides; Lecture notes; Lab exercises with solutions;

Exam: Compulsory oral exam; Individual essay;

The course is assessed through a compulsory oral examination. Each student brings to the oral exam a personal lab book prepared throughout the computational laboratory sessions. The lab book takes the form of a PowerPoint presentation (pptx) compiled individually by each student. It documents the exercises carried out with GROMACS session by session: the simulations performed, the analyses conducted, the results obtained, and the student's own interpretation of the findings. Typical content includes conformational analysis, energy minimisation, equilibrium and non-equilibrium molecular dynamics, steered MD and force-extension curves, simulated annealing, and free energy calculations. During the oral exam, the lab book serves as the starting point for discussion. However, the exam covers the full course programme: students are expected to master the theoretical foundations, the computational methods, and the applications presented in lectures, and may be asked questions on any topic covered in the course.

In addition to the message sent by the online system, students with disabilities or Specific Learning Disorders (SLD) are invited to directly inform the professor in charge of the course about the special arrangements for the exam that have been agreed with the Special Needs Unit. The professor has to be informed at least one week before the beginning of the examination session in order to provide students with the most suitable arrangements for each specific type of exam.