Are you asking which amino acid of the ligand interacts with which amino acid of another protein or are you asking if two proteins actually interact?  There are numerous methods to determine if there is an interaction (analytical ultrcentrifugation, pull down, size exclusion, native gels, SEC HPLC, and others) and perhaps the ultimate method to determine which are the interacting amino acids is x-ray crystallography of co-crystals.  But there is a tremendous amount of literature on the subject matter that is available through literature searches.

It depends of the system but to get the amino acid level of detail for a protein-ligand interaction I can see 3 way to go.

(1) NMR. It is a great tool for this purpose especially If the protein of interest is already assigned. you can monitor chemical shifts perturbations upon ligand addition and identify amino acids involved in binding the ligand 

(2) X-ray Cristallography. If you can get the structure of the complex, you would have all the level of detail you need to understand how the protein and ligand interact together.

(3) Site directed mutagenesis coupled with your method of choice to probe interaction (pull-down, co-ip, size exclusion chromatography etc). it would require you to have assumptions about how the protein and ligand may interact to design your mutation and inhibit the interaction. Maybe you can have clues from the literature or from a similar system. But care should be taken that designed mutations don't just mess with the protein structure itself.

I hope that helps.

As for "what is protein-ligand interaction" sub-question . . . Protein and ligand can be said to "interact" if they "sense/feel" each other. The interaction will be favorable if they like each other more than hate and unfavorable if they hate each other more than like.

There are two (among others) useful (at some levels of conceptualization) concepts about matter (which itself is a concept): geometry and energy. If the protein is in Boston but the ligand in Melbourne there would be very little interaction between the two. The interaction, which can be described via van der Waals and electrostatic potentials, has strong distance-dependence.

Hence the usefulness of having atomic resolution structure of the complex, which shows the ligand binding site (the first shell of amino acid residues surrounding the ligand). However, the further one goes from the binding site the harder it is to quantify the contribution of each amino acid residue to the ligand binding, while in the grand total even very distant amino acid residues can have a sizable effect on the ligand binding, e.g. by modulating the shape and accessibility of the ligand binding site. Also, the further one goes from the binding site, the larger the number of amino acid residues and hence the complexity of the problem.

If u are asking computationally, we can study the interactions between protein and ligand using LigPlot + tool.

Thank you sir...

It's really helpful.@ Remy Le Meur

PLIP and PDBsum (generate) are great bioinformatics tools to study Protein-ligand interactions in X-ray or docked structures