REM out (Put // in front of the lines) the following lines for the province you want to lock. I'm using Rome as an example.

Code:
//SetNeighbours:: ID_ROME	ID_NAPLES	ID_PAPAL_STATES	ID_TUSCANY	ID_TYRRHENIAN_SEA	
		
//SetBorderInfo::	ID_ROME	ID_TUSCANY	13864	15672	0	ARID	AT_SOUTHERN_EUROPEAN	INLAND	HILLY	NO_RIVER
//SetBorderInfo::	ID_ROME	ID_PAPAL_STATES	14432	15912	0	ARID	AT_SOUTHERN_EUROPEAN	INLAND	HILLY	NO_RIVER
//SetBorderInfo::	ID_NAPLES	ID_ROME	14824	16472	0	ARID	AT_SOUTHERN_EUROPEAN	INLAND	HILLY	NO_RIVER
//SetBorderInfo::	ID_PAPAL_STATES	ID_ROME	14248	15984	0	ARID	AT_SOUTHERN_EUROPEAN	INLAND	HILLY	NO_RIVER
//SetBorderInfo::	ID_TUSCANY	ID_ROME	13904	15808	0	ARID	AT_SOUTHERN_EUROPEAN	INLAND	HILLY	NO_RIVER
//SetBorderInfo::	ID_TYRRHENIAN_SEA	ID_ROME	14128	16400	0	ARID	AT_SOUTHERN_EUROPEAN	COAST	HILLY	NO_RIVER
//SetBorderInfo::	ID_ROME	ID_NAPLES	15064	16456	0	ARID	AT_SOUTHERN_EUROPEAN	INLAND	HILLY	NO_RIVER

//SetAttributes::	ID_ROME				"Rome"			    0		CATHOLIC_CULTURE	ARID	AT_SOUTHERN_EUROPEAN	-1			400		"Rome Castle_xzy"			INLAND	HILLY	NO_RIVER	TRUE
Modify the following lines to remove ID_ROME

Code:
SetNeighbours:: ID_TUSCANY	ID_GENOA	ID_ROME	ID_PAPAL_STATES	ID_VENICE	ID_MILAN	ID_LIGURIAN_SEA	ID_TYRRHENIAN_SEA
SetNeighbours:: ID_PAPAL_STATES	ID_TUSCANY	ID_ROME	ID_NAPLES	ID_VENICE	ID_ADRIATIC_OCEAN			//SetNeighbours:: ID_ROME	ID_NAPLES	ID_PAPAL_STATES	ID_TUSCANY	ID_TYRRHENIAN_SEA
SetNeighbours:: ID_NAPLES	ID_ROME	ID_SICILY	ID_PAPAL_STATES	ID_ADRIATIC_OCEAN ID_TYRRHENIAN_SEA ID_STRAITS_SICILY	ID_IONIAN_SEA
SetNeighbours:: ID_TYRRHENIAN_SEA	ID_TUSCANY	ID_ROME	ID_NAPLES	ID_SARDINIA	ID_CORSICA	ID_STRAITS_SICILY	ID_WESTERN_MED	ID_LIGURIAN_SEA
Rome should now no longer be selectable, much less eligable to invade.

I also removed all units from the region. It works fine with the faction leader having Rome as a starting position. If you remove Papal States from FN_PAPIST, then you will effectively isolate the Pope in Rome. Just remember that this will be a challenge for Muslim and Orthodox factions, as they will have no way to "negotiate" a truce to a Crusade except by invading the province with the Chapter House.